TW202333670A - Compound for inhibiting and degrading irak4, and pharmaceutical composition and pharmaceutical application thereof - Google Patents

Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate thereof, and use thereof in IRAK4-related diseases such as autoimmune diseases, inflammatory diseases or cancers. B-L-K(I).

Description

Compounds that inhibit and degrade IRAK4 and pharmaceutical compositions and pharmaceutical applications thereof

The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in IRAK4-related diseases such as tumors or autoimmune diseases.

Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites and play key roles in various aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in controlling the signaling events that initiate cell growth, differentiation, and survival in response to extracellular mediators or stimuli such as growth factors, cytokines, or chemokines. Generally speaking, protein kinases are divided into two categories, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.

Interleukin-1 receptor kinase 4 (IRAK4) is a serine/threonine-specific protein kinase, a member of the tyrosine-like kinase (TLK) family, and an interleukin-1, 18, 33 receptor and Toll-like receptor. A key node involved in the innate immune response. After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they are recruited to form the MyD88:IRAK4:IRAKl/2 multi-protein complex, leading to the phosphorylation of IRAK1/2, mediating a series of downstream signaling, thereby initiating p38 and JNK and NF-kB signaling pathways, ultimately leading to the expression of pro-inflammatory cytokines. Clinical pathology studies have shown that individuals with IRAK4 mutations have a protective effect against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can survive into adulthood, with a reduced risk of infection as they age. Therefore, IRAK4 has become an important therapeutic target and has attracted extensive research and development interest.

PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind to targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of cells, causing the degradation of targeting proteins, and can effectively reduce targeting Protein content in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years.

Therefore, it is necessary to develop novel IRAK4 inhibitors and E3 ubiquitin ligase PROTAC drugs for the treatment of IRAK4-related diseases.

The purpose of the present invention is to provide a compound with a novel structure, good efficacy, high bioavailability, safety, and the ability to inhibit or degrade IRAK4 for the treatment of IRAK4-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

The present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I), B-L-K (I);

In certain embodiments, B is selected from or ;

In certain embodiments, B1 and B3 are each independently selected from C _6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, and the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, B1 and B3 are each independently selected from pyrazolyl, oxazolyl, dioxazolyl, oxadiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl, thienyl, Thiazolyl, thiadiazolyl, pyridyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienopyrazinyl, benzimidazolyl, pyridotriazolyl, pyrimidopyrazolyl, imidazole Pyridazinyl, pyridopyrazolyl, pyrrolopyridazinyl or ;

In certain embodiments, B1, B3 are selected from , , ;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , -N(R ^b21 ) ₂ , C _6-10 aromatic base, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group, the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted by 0 to 4 Selected from H, F, Cl, Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _1-4 alkoxy substituted by a C _3-6 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclyl group or a substituent of R ^b7a , the heteroaryl group or heterocyclyl group contains 1 to 4 optional Heteroatoms from O, S, N;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , CHF ₂ , CH ₂ F, methyl, Ethyl, methoxy, ethoxy, phenyl, pyrrolyl, pyridyl, morpholinyl, , , , , , , , , , , , , , , , , , , , the methyl group, ethyl group, methoxy group, ethoxy group, phenyl group, pyrrolyl group, pyridyl group and morpholinyl group are optionally further selected from 0 to 4 from H, F, Cl, Br, I, OH, CN, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, C _1-4 alkyl, C _1-4 alkyl Substituted by oxygen group, C _3-6 cycloalkyl group or R ^b7a substituent;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from the group consisting of azetidinyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, 2-oxa-5-aza Heterobicyclo[2.2.1]heptyl, the R ^b1 and R ^b7 are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CN, CF ₃ , NH ₂ , NHC _{1 -4} alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or R Substituted with a substituent of ^b7a , the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from azetidinyl, azetipentyl, piperidinyl, piperazinyl, morpholinyl, 2-oxa-5-aza Bicyclo[2.2.1]heptyl, the R ^b1 and R ^b7 are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CN, CF ₃ , NH ₂ , NHC _{1- 4} alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, -C _{1- 4Alkylene} -OH, C _1-4 alkyl, C _1-4 alkoxy, -CH ₂ -OC _1-4 alkyl, -CH ₂ -C _3-6 cycloalkyl, -OC _3-6 Cycloalkyl, -NH-C _3-6 cycloalkyl, C _3-6 cycloalkyl, -CH ₂ -4 to 7-membered heterocycloalkyl, -O-4 to 7-membered heterocycloalkyl, -NH -Substituted with a 4- to 7-membered heterocycloalkyl group or a 4- to 7-membered heterocycloalkyl substituent, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from azetidinyl, azetipentyl, phenyl, pyrrolyl, pyridyl, morpholinyl, , , , , , , , , , , , , , , , , , , ;

In certain embodiments, R ^b1 and R ^b7 are each independently selected from , , , , , , or ;

In certain embodiments, R ^b1 and R ^b7 are optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, CN or R ^b7a ;

In certain embodiments, R ^b7a is selected from C _1-4 alkyl, -C _3-6 cycloalkyl, 4-10 membered heterocyclyl, -C _1-4 alkylene-C _3-6 cycloalkyl Base, -C _1-4 alkylene-4-10 membered heterocyclyl, -OC _3-6 cycloalkyl, -O-4-10 membered heterocyclyl, -NH-C _3-6 cycloalkyl, -NH-4-10-membered heterocyclyl, -N(C _1-4 alkyl)-C _3-6 cycloalkyl, -N(C _1-4 alkyl)-4-10-membered heterocyclyl, so The above-mentioned R ^b7a is optionally composed of 1 to 4 selected from H, F, Cl, Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, C _{1- 4} alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4-10 membered heterocyclyl substituents, the heterocyclyl contains 1 to 4 selected from O, S, N of heteroatoms;

In certain embodiments, R ^b7a is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl , azepanyl, piperazinyl, morpholinyl, oxetanyl, oxanyl, oxanyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -Cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -azetidinyl, -CH ₂ -azetidine, -CH ₂ -piperazinyl, - CH ₂ -morpholinyl, -CH ₂ -oxetanyl, -CH ₂ -oxetanyl, -CH ₂ -oxetanyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azetidinyl, -O-azetidine, -O-piperazinyl, -O-? Phenyl, -O-oxetanyl, -O-oxetanyl, -O-oxetanyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-azetidinyl, -NH-azetipentyl, -NH-azetidinyl, -NH-piperazinyl, -NH-morpholinyl, -NH-oxygen Heterocyclylbutyl, -NH-oxanyl, -NH-oxanyl, the R ^b7a is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CN, Substituted with substituents of CF ₃ , C(=O)OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, and 4-10 membered heterocyclyl, the heterocyclic The base contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^b7a is selected from CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CN, CH ₂ OH, CH ₂ OCH ₃ , methyl, ethyl, -CH ₂ -cyclopropyl, -CH ₂ -Azetidinyl, -CH ₂ -oxetanyl, -O-cyclopropyl, -O-azetidinyl, -O-oxetanyl, -NH-cyclopropyl, -NH-azetidinyl, -NH-oxetanyl, , ;

In certain embodiments, R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, OH, -C(=O)N(R ^b21 ) ₂ , -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , C _6-10 aryl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group, the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group or heterocyclic group The ring group is optionally further selected from 0 to 4 members from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C Substituted with substituents of _1-4 alkoxy, C _3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the heteroaryl or heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;

In certain embodiments, R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, CF ₃ , CHF ₂ , OH, NH ₂ , NH (methyl), NH (ethyl). base), NH (propyl), NH (isopropyl), N (methyl) ₂ , N (ethyl) ₂ , CN, methyl, ethyl, methoxy, ethoxy, propoxy, Isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyl The baseoxy group, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

In certain embodiments, R ^b21 is each independently selected from H, C1-6 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered hetero Aryl or 4-10-membered heterocyclyl, the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted by 0 to 4 selected from H, F, Cl , Br, I, OH, =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy substituents Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

In certain embodiments, L is selected from the group consisting of -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1 -Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Cy1-Cy2-Ak3-Cy4-, -Cy1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2 -Cy2-Cy3-Ak4-, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Ak3 -Cy3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3 -, -Cy1-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, - Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak4-Cy4-, - Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4- , -Ak1-Ak2-Ak3-Cy3-Ak4-, -Ak1-Cy1-Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-Ak3-, -Ak1-Cy1-Ak2- Ak3-Ak4-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1- Ak2-Ak3-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3- Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH ₂ ) _q -, O, -(CH ₂ ) _q NR ^L -, NR ^L C=O, C=ONR ^L , C=O, -R ^L C=CR ^L -, C≡C or bond;

In certain embodiments, Ak1 _, Ak2, _{Ak3 ,} Ak4, Ak5 are each independently selected from O, C≡C, _{CH2 , CH2CH2 , CH2CH2CH2 , CH2CH2CH2CH2} , CH ₂ N(CH ₃ ), CH ₂ CH ₂ N(CH ₃ ), N(CH ₃ ), NH, C(=O), C(=O)N(CH ₃ ), N(CH ₃ )C (=O), C(=O)NH or NHC(=O);

In certain embodiments, R ^L is selected from H or C _1-6 alkyl;

In certain embodiments, R ^L is selected from H, methyl, or ethyl;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from the group consisting of bonds, 4-7-membered heteromonocycles, 4-10-membered heterocyclic rings, 5-12-membered heterospirocycles, 7-10-membered heterocycles, Bridged ring, 3-7 membered monocyclic alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 Aryl group, the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring or heterobridged ring are optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, C(=O)OH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, or C _1- Substituted with ₄ alkoxy substituents, the heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, Cy1, Cy2, Cy3 and Cy4 are each independently selected from the group consisting of bonds, 4-7 membered nitrogen-containing heteromonocycles, 4-10 membered nitrogen-containing heterocycles, 5-12 membered nitrogen-containing heterospirocycles , 7-10 membered nitrogen-containing heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered paracycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, 5-10 Member heteroaryl or 6-10 membered aryl, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl group is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, C(=O)OH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _{1- 4} alkyl or C _1-4 alkoxy substituent, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring or heteroaryl group contains 1 to 4 selected from O, S , N heteroatoms;

In certain embodiments, Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aza Cyclobutyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropyl Propylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutyl Spirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidine, cyclopropylazetidine Heterocyclohexyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclopentyl azetidinyl, cyclopentyl azetidine Pentyl, cyclopentyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, azetidinyl azetidinyl, Azetidinyl azepanyl, azetidinyl azepanyl, azetidinyl azepanyl, azetidinyl azepanyl, azetidinyl Azacyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidine Heterocyclopentyl, cyclopentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, azetidinylspiroazetidine base, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidine Cyclohexylspiroazacyclohexyl, , , , , , , , , , , , , , , , , , , or , , when substituted, optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , C(=O)OH, CN, =O, C _1-4 alkyl, Substituted with halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, or C _1-4 alkoxy substituents;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following substituted or unsubstituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , when substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF ₃ , methyl, =O, hydroxymethyl, C(=O)OH, CN or NH ₂ ;

In certain embodiments, L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , ;

In certain embodiments, each J ₁ is independently selected from , , ;

In certain embodiments, each _J2 is independently selected from , , , , , , , , , , , ;

In certain embodiments, each J ₃ is independently selected from , , , , , ;

In certain embodiments, each J ₄ is independently selected from , , , , , ;

In certain embodiments, each J ₅ is independently selected from ;

In certain embodiments, L is selected from , R ^d is selected from H or D, and at least one R ^d is selected from D, d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

In certain embodiments, L is selected from the groups shown in Table L-1, wherein the left side of the group is connected to B;

Table L-1 L group ;

In certain embodiments, L is selected from , R ^L1a is each independently selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, preferably F, Cl, Br, CN, OH, methyl, ethyl, hydroxymethyl , methoxy or ethoxy, m is selected from 0, 1, 2, 3 or 4;

In certain embodiments, L is selected from , , , , , , , , , , , , , , , , , , , , , , ;

In certain embodiments, K is selected from , , or ;

In certain embodiments, R ^k1 is each independently selected from H, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered hetero Cycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CF ₃ , C _1- Substituted with substituents of ₆ alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl;

In certain embodiments, each R ^k1 is independently selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetanyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, the Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetanyl, piperidyl, oxetanyl, Oxanyl and oxanyl are optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy Substituted with substituents of base, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl;

R ^k1 is each independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, oxetanyl, -CH ₂ CF ₃ , -CH(CH ₃ )CF ₃ , - CH(CH ₃ )-cyclopropyl, -CH ₂ -cyclopropyl _, -CH 2 -vinyl, -CH ₂ -ethynyl, -CH ₂ CH ₂ -methoxy, -CD ₃ ;

In certain embodiments, R ^k2 , R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C(= O) NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the alkyl or alkoxy is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, Substituted by NH ₂ substituent;

Or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocyclic ring or a 3-7 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, =O, NH ₂ , CN, C(=O)OH, C(=O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^k2 , R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C(= O)NH ₂ , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy or ethoxy is optionally further substituted by 0 to 4 selected from H, F, Cl, Substituted by Br, I, OH, NH ₂ substituents;

In certain embodiments, R ^k2 and R ^k3 are each independently selected from H or F;

In certain embodiments, K is selected from ;

In certain embodiments, K is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

In certain embodiments, 0 to 50 H in the compound represented by general formula (I) are optionally replaced by 0 to 50 D;

In certain embodiments, 0 to 30 H in the compound represented by general formula (I) are optionally replaced by 0 to 30 D;

In certain embodiments, 0 to 20 H in the compound represented by general formula (I) are optionally replaced by 0 to 20 D;

In certain embodiments, 0-20 H's in L are optionally replaced by 0-20 D's;

In certain embodiments, 0 to 10 H in the compound represented by general formula (I) are optionally replaced by 0 to 10 D;

In certain embodiments, 0 to 10 H in -L-K are optionally replaced by 0 to 10 D;

In certain embodiments, 0 to 10 H's in L are optionally replaced by 0 to 10 D's;

In certain embodiments, 0 to 10 H's in K are optionally replaced by 0 to 10 D's;

In certain embodiments, 0 to 20 H in L are optionally replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 D replacements;

In certain embodiments, 0 to 10 H in L are optionally replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D;

In certain embodiments, 0 to 10 H in K are optionally replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D;

In certain embodiments, 0 to 10 H in -L-K are optionally replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D;

In certain embodiments, n is selected from 0, 1, 2, 3, or 4;

In certain embodiments, q is selected from 0, 1, 2, 3, or 4;

In certain embodiments, n1, n2, and n6 are each independently selected from 0, 1, 2, or 3;

In certain embodiments, p2, p3 are each independently selected from 0, 1, 2, 3 or 4;

In certain embodiments, p2 or p3 are each independently selected from 0, 1, or 2.

As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH ₂ ) _q -, O, -(CH ₂ ) _q NR ^L -, NR ^L C=O, C=ONR ^L , C=O, - R ^L C=CR ^L -, C≡C or bond;

R ^L is selected from H or C _1-6 alkyl;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from the group consisting of bonds, 4-7-membered heteromonocyclic rings, 4-10-membered heterocyclic rings, 5-12-membered heterospirocyclic rings, 7-10-membered heterobridged rings, and 3-7-membered heterocyclic rings. Monocyclic alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the aryl base, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, C(= O)OH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, or C _1-4 alkoxy substituents Substituted, the heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N;

B is selected from or ;

B1 and B3 are each independently selected from the group consisting of C _6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl. The heteroaryl or heterocyclyl contains 1 to 4 selected from O, Heteroatoms of S and N;

R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy group, C _3-6 cycloalkyl group, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , -N(R ^b21 ) ₂ , C _6-10 aryl group, 5-10 membered hetero group Aryl or 4-10 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further optionally further substituted by 0 to 4 selected from H, F, Cl , Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 ring Alkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or R ^b7a substituent, the heteroaryl or heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

R ^b7a is selected from C _1-4 alkyl, -C _3-6 cycloalkyl, 4-10 membered heterocyclyl, -C _1-4 alkylene, -C _3-6 cycloalkyl, -C _1-4 Alkylene-4-10-membered heterocyclyl, -OC _3-6- membered cycloalkyl, -O-4-10-membered heterocyclyl, -NH-C _3-6- membered cycloalkyl, -NH-4-10-membered Heterocyclyl, -N(C _1-4 alkyl)-C _3-6 cycloalkyl, -N(C _1-4 alkyl)-4-10 membered heterocyclyl, the R ^b7a is optionally replaced by 1 To 4 selected from H, F, Cl, Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _1- Substituted with substituents of ₄ alkoxy, C _3-6 cycloalkyl, and 4-10 membered heterocyclyl, the heterocyclyl containing 1 to 4 heteroatoms selected from O, S, and N;

R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, OH, -C(=O)N(R ^b21 ) ₂ , -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , C _{6 -10} aryl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group, the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group or heterocyclyl group is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituent, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;

R ^b21 is each independently selected from H, C _1-6 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl or 4-10 Member heterocyclyl group, the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group or heterocyclic group is optionally further optionally substituted by 0 to 4 selected from H, F, Cl, Br, I, OH , =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy substituents, the Heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

n is selected from 0, 1, 2, 3 or 4;

K is selected from , , or ;

^Rk1 is each independently selected from H, C _1-4 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, the alkyl The base, cycloalkyl, and heterocycloalkyl are optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CF ₃ , C _1-6 alkyl, C _1- Substituted with substituents of ₆ alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl;;

R ^k2 and R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C(=O)NH ₂ , C _{1 -4} alkyl or C _1-4 alkoxy, the alkyl or alkoxy is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH ₂ ;

Or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-6 membered carbocyclic ring or a 3-7 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, =O, NH ₂ , CN, C(=O)OH, C(=O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

q is selected from 0, 1, 2, 3 or 4;

n1, n2 and n6 are each independently selected from 0, 1, 2 or 3;

p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

Optionally, 0 to 50 H's in the compound represented by general formula (I) are replaced by 0 to 50 D's.

As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

Cy1, Cy2, Cy3 and Cy4 are each independently selected from bond, 4-7 membered nitrogen-containing heteromonocyclic ring, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered nitrogen-containing heterospirocyclic ring, 7-10-membered nitrogen-containing heterocyclic ring Heterobridged ring, 3-7 membered monocyclic alkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6- 10-membered aryl group, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring, cycloalkyl, aryl or heteroaryl group is optionally further substituted by 0 to 4 selected from H, F, Cl, Br , I, OH, C(=O)OH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, or C _{1 -4} substituted by alkoxy substituents, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N;

The remaining definitions are the same as in the first embodiment of the invention.

As the third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

R ^L is selected from H, methyl or ethyl;

Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidine Pentyl, piperidyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl Butylcyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl , cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidine, cyclopropylazetidine, cyclobutyl Azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclopentyl azetidinyl, cyclopentyl azetidinyl, cyclopenta Azetidinyl, cyclohexylazetidinyl, cyclohexylazetipentyl, cyclohexylazetidinyl, azetidinylazetidinyl, azetidinyl Cyclopentyl, azetidinyl and azepanyl, azetanyl and azepanyl, azetanyl and azepanyl, azetanyl and azepanyl, ring Butylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentyl Spiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinyl Spiroazacyclopentyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl , , , , , , , , , , , , , , , , , , , or , , when substituted, optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , C(=O)OH, CN, =O, C _1-4 alkyl, Substituted with halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, or C _1-4 alkoxy substituents;

B1 and B3 are each independently selected from pyrazolyl, oxazolyl, dioxazolyl, oxadiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl ,pyridyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienopyrazinyl, benzimidazolyl, pyridotriazolyl, pyrimidopyrazolyl, imidazopyridazinyl, pyrido Pyrazolyl, pyrrolopyridazinyl or ;

R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, methoxy, Ethoxy, phenyl, pyrrolyl, pyridyl, morpholinyl, , , , , , , , , , , , , , , , , , , , the methyl group, ethyl group, methoxy group, ethoxy group, phenyl group, pyrrolyl group, pyridyl group, and morpholinyl group are optionally further selected from 0 to 4 from H, F, Cl, Br, I, OH, CN, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, C _1-4 alkyl, C _1-4 alkyl Substituted by oxygen group, C _3-6 cycloalkyl group or R ^b7a substituent;

Or R ^b1 and R ^b7 are each independently selected from azetidinyl, azetipentyl, piperidinyl, piperazinyl, morpholinyl, 2-oxa-5-azabicyclo [2.2.1] Heptyl group, the R ^b1 and R ^b7 are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CN, CF ₃ , NH ₂ , NHC _1-4 alkyl, N( C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, -C _1-4 alkylene-OH , C _1-4 alkyl, C _1-4 alkoxy, -CH ₂ -OC _1-4 alkyl, -CH ₂ -C _3-6 cycloalkyl, -OC _3-6 cycloalkyl, -NH -C _3-6 cycloalkyl, C _3-6 cycloalkyl, -CH ₂ -4 to 7 membered heterocycloalkyl, -O-4 to 7 membered heterocycloalkyl, -NH-4 to 7 membered hetero Substituted with cycloalkyl and 4 to 7-membered heterocycloalkyl substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, CF ₃ , CHF ₂ , OH, NH ₂ , NH (methyl), NH (ethyl), NH (propyl) ), NH (isopropyl), N (methyl) ₂ , N (ethyl) ₂ , CN, methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, ? Phyllinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl , piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl , C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

^Rk1 is each independently selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetanyl, piperidinyl, oxetanyl, oxolyl, oxygen Heterocyclohexyl is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl , substituted by allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl substituents;

R ^k2 and R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C(=O)NH ₂ , methyl , ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy or ethoxy is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, NH Substituted by the substituent of ₂ ;

p2 or p3 are each independently selected from 0, 1 or 2;

The remaining definitions are the same as in the first or second embodiment of the invention.

As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following groups: bond or substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , when substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF ₃ , methyl, =O, hydroxymethyl, C(=O)OH, CN or NH ₂ ;

B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

The remaining definitions are the same as in the first, second or third embodiment of the present invention.

As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L is selected from the group consisting of bonds, -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1-Ak2-Cy2-, - Cy1-Cy2-Ak3-, -Cy1-Cy2-Ak3-Cy4-, -Cy1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4- , -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Cy3-Ak4-, - Cy1-Ak2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2- Cy3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, -Cy1-Ak2-Cy2-Ak3 -Cy3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak4-Cy4-, -Ak1-Cy1-Ak2-Cy2 -, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4-, -Ak1-Ak2-Ak3 -Cy3-Ak4-, -Ak1-Cy1-Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-Ak3-, -Ak1-Cy1-Ak2-Ak3-Ak4-, -Ak1 -Cy1-, -Ak1-Cy1-Ak2-Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Cy4 -Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3-Ak4-, -Cy1-Ak2 -Cy2-Ak3-Cy3-Ak4-;

Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from O, C≡C, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ , CH ₂ N(CH ₃ ), CH ₂ CH ₂ N(CH ₃ ), N(CH ₃ ), NH, C(=O), C(=O)N(CH ₃ ), N(CH ₃ )C(=O), C( =O)NH or NHC(=O);

The remaining definitions are the same as the first, second, third or fourth embodiment of the present invention.

As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , ;

J ₁ are each independently selected from , , ;

J ₂ are each independently selected from , , , , , , , , , , , ;

J ₃ are each independently selected from , , , , , ;

J ₄ are each independently selected from , , , , , ;

J ₅ are each independently selected from ;

Alternatively, L is selected from ;

R ^d is selected from H or D, and at least one R ^d is selected from D;

d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

The remaining definitions are the same as the first, second, third, fourth or fifth embodiment of the present invention.

As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L is selected from the groups shown in Table L-1, where the left side of the group is connected to B;

The remaining definitions are the same as the first, second, third, fourth, fifth or sixth embodiment of the present invention.

As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

K is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

The remaining definitions are the same as the first, second, third, fourth, fifth, sixth or seventh embodiment of the present invention.

The present invention relates to one of the following compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from one of the following structures in Table P-1:

Table P-1 Compound structure table .

The present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutically acceptable carrier. .

The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or pharmaceutical composition used in the preparation of treatment with IRAK4 activity or Application in drugs for expression-related diseases.

The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or pharmaceutical composition used in the preparation of treatment and inhibition or degradation Applications in drugs for IRAK4-related diseases.

The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and the diseases are selected from autoimmune diseases. , inflammatory diseases or cancer.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which contains a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, Pharmaceutically acceptable salts or co-crystals and pharmaceutical excipients. The pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation specification").

The present invention also provides a method for treating diseases in a mammal, which includes administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolism products, pharmaceutically acceptable salts or co-crystals or pharmaceutical compositions. In some embodiments, mammals of the present invention include humans.

The "effective amount" or "therapeutically effective amount" used in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate to some extent the disease or condition being treated (such as autoimmune diseases, inflammatory diseases or cancer). In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6 -600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg , 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50 -500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg , 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100 -400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg , 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1 -200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg , 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;

In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, Pharmaceutically acceptable salts or co-crystals.

A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable Salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably autoimmune disease, inflammatory disease or cancer.

A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to 1 -A daily dose of 1500 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10- 800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg/ Days, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day, 1500mg/day.

The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or co-crystals, the amount of the compound of the present invention or its stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as the amount in the above-mentioned pharmaceutical composition same.

In the present invention, the amount of the compound of the invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is converted in each case in the form of free alkaloids.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and the isotopes of hydrogen include protium (H), deuterium (D, (also called heavy hydrogen), tritium (T, also called superheavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"CN" refers to the cyano group.

"Halogen" refers to F, Cl, Br or I.

"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is simply referred to as "halogenated."

"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including ‒(CH ₂ ) _v ‒ (v is an integer from 1 to 10). Examples of alkylene include but do not Limited to methylene, ethylene, propylene, butylene, etc.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups can be monovalent, divalent, trivalent or tetravalent

"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3‒butenyl, 1‒pentenyl, 2‒pentenyl, 3‒pentenyl, 4‒pentenyl, 1‒methyl‒1‒butenyl, 2‒methyl‒1‒butenyl Alkenyl, 2‒methyl‒3‒butenyl, 1‒hexenyl, 2‒hexenyl, 3‒hexenyl, 4‒hexenyl, 5‒hexenyl, 1‒methyl‒1 ‒Pentenyl, 2‒methyl‒1‒pentenyl, 1‒heptenyl, 2‒heptenyl, 3‒heptenyl, 4‒heptenyl, 1‒octenyl, 3‒octenyl base, 1‒nonenyl, 3‒nonenyl, 1‒decenyl, 4‒decenyl, 1,3‒butadiene, 1,3‒pentadiene, 1,4‒pentadiene and 1,4‒hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms. , including but not limited to 2 to 6 carbon atoms in the main chain, and 2 to 4 carbon atoms in the main chain. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1‒propynyl, 2 ‒propynyl, 1‒butynyl, 2‒butynyl, 3‒butynyl, 1‒pentynyl, 2‒pentynyl, 3‒pentynyl, 4‒pentynyl, 1‒methyl Base‒1‒butynyl, 2‒methyl‒1‒butynyl, 2‒methyl‒3‒butynyl, 1‒hexynyl, 2‒hexynyl, 3‒hexynyl, 4‒ Hexynyl, 5‒hexynyl, 1‒methyl‒1‒pentynyl, 2‒methyl‒1‒pentynyl, 1‒heptynyl, 2‒heptynyl, 3‒heptynyl, 4‒heptynyl, 1‒octynyl, 3‒octynyl, 1‒nonynyl, 3‒nonynyl, 1‒decynyl, 4‒decynyl, etc.; the alkynyl group can be monovalent, Bivalent, trivalent or tetravalent.

"Alkoxy" refers to substituted or unsubstituted ‒O‒alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.

"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclo Pentyl‒3‒alkenyl, cyclohexyl, 1‒cyclohexyl‒2‒alkenyl, 1‒cyclohexyl‒3‒alkenyl, cyclohexenyl, benzene ring, naphthalene ring, , , or . "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a monocyclic ring with 3 to 8 members, or a monocyclic ring with 4 to 12 members. Bicyclic or 10 to 15-membered tricyclic ring system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3‒dioxanyl, 1,4‒dioxanyl, 1,3‒dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phenyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl , benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1 ]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, , , , , , , , , , , , , or . "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Can contain 0 to 5 heteroatoms selected from N, O or S(=O) _n (n is 0, 1 or 2). Non-limiting examples include: . "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.

"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S(=O) _n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: , , , "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain 0 or more double bonds and any ring in the ring system. It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) _n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include , , , , , cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.

"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article have the same definition as spirocycle.

"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms. The definition of "carbocyclic ring", "carbocyclic ring group", "carbocyclic ring group" or "carbocyclic ring group" appearing in this article is consistent with that of carbocyclic ring.

"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged carbocyclic ring group", "bridged carbocyclic ring group" or "carbon bridged ring group" appearing in this article are consistent with those of the bridged ring.

"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to the "heterocyclyl" or "heterocycle" of a monocyclic system. The heterocyclyl, "monocyclic heterocycle" appearing in this article "Basic" or "heteromonocyclyl", its definition is consistent with heterocyclic.

"Heterocyclic ring", "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring radical" refers to a "heterocyclic ring" containing heteroatoms. The definitions of heterocyclic ring, "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring group" appearing in this article are consistent with those of the heterocyclic ring group.

"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing heteroatoms. Heterospirocycle, "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" appearing in this article have the same definition as spirocycle.

"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" refers to a "bridged ring" containing heteroatoms. The definition of hetero-bridged ring, "hetero-bridged cyclyl", "bridged-ring heterocyclyl" or "hetero-bridged cyclyl" appearing in this article is consistent with that of bridged ring.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, An "aryl group" or "aryl ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.

"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 optional heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O) _n , n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include and . Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.

"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, ‒(CH ₂ ) _m ‒C(=O)‒R ^a , ‒O‒(CH ₂ ) _m ‒ C(=O)‒R ^a , ‒(CH ₂ ) _m ‒C(=O)‒NR ^b R ^c , ‒(CH ₂ ) _m S(=O) _n R ^a , ‒(CH ₂ ) _m ‒ene Base ‒R ^a , OR ^d or ‒(CH ₂ ) _m ‒Alkynyl ‒R ^a (where m and n are 0, 1 or 2), arylthio group, thiocarbonyl group, silyl group or ‒NR ^b R ^c and other groups, wherein R ^b and R ^c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoro Methanesulfonyl group, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclic group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, Cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclyl, spirocyclyl or paracyclyl.

"Containing 1 to 4 heteroatoms selected from O, S, and N" means containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, and X is selected from any integer between 1 and 10. For example, "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. For example, "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F replaced by base.

The ring of members .Y member’s ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7-member heteromonocyclic ring" refers to a heterocyclic monocyclic ring with 4, 5, 6, or 7 members, and "5-10-membered heterocyclic ring" refers to a heterocyclic ring with 5, 6, 7, or 8 members. , 9-membered or 10-membered heterocyclic rings.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" means that the compounds of the present invention retain the biological effectiveness and properties of free acids or free alkaloids, and the free acids are combined with non-toxic inorganic alkaloids or organic alkaloids. The free salt is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and A mixture of other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.

"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure states of API and CCF are uniform at room temperature. It is a solid and has a fixed stoichiometric ratio between its components. A eutectic is a multi-component crystal that includes both a two-member eutectic formed between two neutral solids and a multi-member eutectic formed between a neutral solid and a salt or solvate.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

"IC50" is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) by half.

The technical solution of the present invention will be described in detail below with reference to the examples, but the protection scope of the present invention includes but is not limited thereto.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTech, and Bailingwei Technology, etc. company.

The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD ), the internal standard is tetramethylsilane (TMS);

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Thin layer chromatography (TLC) uses silica gel plates with specifications of 0.15 mm-0.20 mm. Thin layer chromatography separation and purification products use specifications of 0.4 mm. - 0.5 mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

Reagents and solvents abbreviations:

Dess-Martin oxidizing agent: (1,1,1-triacetyloxy)-1,1-dihydro-1,2-benzoiodide-3(1H)-one (CAS number: 87413-09-0) ; TBSOTf: tert-butyldimethylsilyl triflate; rac-BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (CAS number: 98327-87-8); Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium (CAS number: 51364-51-3); DMA: N,N-dimethylacetamide; DMF: N,N-dimethylmethane Amide; DCM: dichloromethane; MeOH: methanol; NMI: N-methylimidazole;

TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

Preparation of intermediate 1

Step One: Preparation of 1-B

Dissolve 1-A (7.5 g, 32.4 mmol) in THF (120 mL), cool to 0°C, slowly add 1 mol/L borane tetrahydrofuran solution (60 mL, 60 mmol) under nitrogen atmosphere, and react at room temperature for 16 h. Cool the reaction system to 0°C, add 30 mL of a mixed solution of methanol and acetic acid (v/v) = 9:1, concentrate under reduced pressure, add 130 mL of water and 150 mL of ethyl acetate, separate the layers, and use ethyl acetate to separate the water phase. Ester extraction (100 mL × 2), combined organic phases, washed with saturated brine (190 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 23:77), 1-B (5.5 g, yield: 78%) was obtained.

LCMS m/z = 218.1 [M+1] ⁺ .

Step 2: Preparation of 1-C

Add 1-B (5.5 g, 25.3 mmol) into a 250 mL single-neck bottle, add methylene chloride (80 mL), add trifluoroacetic acid (20 mL), and react at room temperature for 4 h. The reaction system was concentrated under reduced pressure, acetonitrile (100 mL) was added to the residue, and N,N-diisopropylethylamine (9.8 g, 75.8 mmol) and 5-chloropyrazolo[1,5-a] were added. Pyrimidine-3-carboxylic acid ethyl ester (5.3 g, 23.49 mmol), react at 60°C for 12 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 41:59) to obtain 1-C (4.6 g, yield: 59% ).

LCMS m/z = 307.1 [M+1] ⁺ .

Step 3: Preparation of 1-D

Add 1-C (2.4 g, 7.8 mmol) to a 100 mL single-neck bottle, add dry DMF (30 mL), add potassium carbonate (3.2 g, 23.15 mmol), cool to 0°C, add methyl iodide (2.2 g, 15.5 mmol), react at room temperature for 16 h. Add water (300 mL) to the reaction system, extract with ethyl acetate (60 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is Silica gel column separation and purification (petroleum ether: ethyl acetate (v/v) = 22:78) gave 1-D (1.3 g, yield: 52%).

LCMS m/z = 321.1 [M+1] ⁺ .

Step 4: Preparation of Intermediate 1

Add 1-D (1.2 g, 3.75 mmol) into a 100 mL single-neck bottle, add methanol (15 mL), water (5 mL), and sodium hydroxide (760 mg, 19 mmol), and react at 50°C for 16 h. Cool the reaction system to room temperature, adjust the pH to 5 with 1 mol/L hydrochloric acid aqueous solution, extract with a mixed solvent of dichloromethane and methanol (v/v) = 10:1 (60 mL×3), and use saturated organic phase to Wash with sodium chloride aqueous solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude intermediate 1 (1.0 g).

LCMS m/z = 293.1 [M+1] ⁺ .

Preparation of intermediate 2

Step One: Preparation of 2-B

Add the hydrochloride of 2-A (1.8 g, 9.4 mmol) into a 100 mL single-neck bottle, add acetonitrile (30 mL), add N,N-diisopropylethylamine (3.6 g, 27.9 mmol) and 5 -Ethyl chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.1 g, 9.31 mmol), react at 60°C for 12 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 68:32) to obtain 2-B (2.3 g, yield: 71% ).

LCMS m/z = 345.1 [M+1] ⁺ .

Step 2: Preparation of Intermediate 2

Add 2-B (2.3 g, 6.68 mmol) into a 250 mL single-neck bottle, add methanol (30 mL), water (10 mL) and sodium hydroxide (1.3 g, 32.5 mmol), and react at 50°C for 16 h. Cool the reaction system to room temperature, adjust the pH to 5 with 1 mol/L hydrochloric acid aqueous solution, extract with a mixed solvent of dichloromethane and methanol (v/v) = 10:1 (80 mL×3), and use saturated organic phase to Wash with sodium chloride aqueous solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude intermediate 2 (1.8 g).

LCMS m/z = 317.1 [M+1] ⁺ .

Preparation of intermediate 3

Step One: Preparation of 3-A

Dissolve 1-C (2.3 g, 7.51 mmol) in 20 mL dichloromethane, add triethylamine (2.28 g, 22.53 mmol), cool to 0°C, add TBSCl (1.70 g, 11.28 mmol), and react at room temperature 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 65:35) to obtain 3-A (1.4 g, yield: 44%).

Step 2: Preparation of intermediate 3

Dissolve 3-A (1.4 g, 3.33 mmol) in a mixed solvent of tetrahydrofuran/water (v/v) = 4:1, add lithium hydroxide monohydrate (699 mg, 16.66 mmol), and react at room temperature for 16 h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid aqueous solution, extract with a mixed solvent of dichloromethane/methanol (v/v) = 10:1 (50 mL×3), and wash the organic phase with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate 3 (0.57 g).

Preparation of intermediate 4

Step One: Preparation of 4-B

Dissolve 4-A (10 g, 85.4 mmol), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (10.49 g, 46.49 mmol) and DIPEA (36.04 g, 278.8 mmol) in In 100 mL acetonitrile, react at 60°C for 12 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 2:3) to obtain 4-B (10 g, yield: 70% ).

LCMS m/z = 307.1 [M+1] ⁺ .

Step 2: Preparation of 4-C

Dissolve 4-B (6 g, 19.59 mmol) in DMF (60 mL), add 0.95 g 60% NaH at 0°C, stir at room temperature for 1 h, then add methyl iodide (4.2 g, 29.59 mmol) at 0°C. , react at room temperature for 16 h. Add water (50 mL) to the reaction system, extract with dichloromethane (100 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether:ethyl acetate ( v/v) = 1:4), 4-C (2 g, yield: 32%) was obtained.

LCMS m/z = 321.1 [M+1] ⁺ .

Step 3: Preparation of Intermediate 4

Add 4-C (2 g, 6.25 mmol) and lithium hydroxide (0.47 g, 19.62 mmol) into a 100 mL single-mouth bottle, add methanol (10 mL) and water (5 mL), and react at 60°C for 4 h. Cool the reaction system to room temperature, add it to 50 mL of water, adjust the pH to 2 with 6 mol/L hydrochloric acid aqueous solution, extract with ethyl acetate (60 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain crude intermediate 4 (2 g).

Preparation of intermediate 5

Step One: Preparation of 5-A

Dissolve 4-B (4 g, 13.06 mmol) and triethylamine (5.29 g, 52.28 mmol) in 50 mL dichloromethane, add TBSCl (3.94 g, 26.14 mmol), and react at room temperature for 16 h. Add 50 mL of water to the reaction system, separate the layers, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 65:35) to obtain 5 -A (2 g, yield: 36%).

Step 2: Preparation of Intermediate 5

Add 5-A (1.8 g, 4.28 mmol) and lithium hydroxide (0.32 g, 13.36 mmol) into a 100 mL single-mouth bottle, add 20 mL methanol and 10 mL water, and react at 60°C for 4 h. Cool the reaction system to room temperature, add 50 mL of water, adjust the pH to 2 with 1 mol/L hydrochloric acid aqueous solution, extract with ethyl acetate (50 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude intermediate 5 (2 g).

Preparation of the hydrochloride salt of intermediate 6 (trans)

Step One: Preparation of 6-B

Dissolve the crude 10d trifluoroacetate (5.57 g) in 40 mL DMA, add sodium bicarbonate (1.49 g, 17.74 mmol), stir at room temperature for 15 min, then add 6-A (3.66 g, 10.66 mmol) ( For the synthesis method, see WO2021158634), 1.2 mL acetic acid and 4 Å molecular sieve (5 g). After stirring at room temperature for 2 h, sodium triacetyloxyborohydride (3.77 g, 17.79 mmol) was added and the reaction was carried out at room temperature for 16 h. Add 150 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 100 mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/ethyl acetate (v /v) = 1:1), obtaining 6-B (3.1 g, yield: 40%).

Step 2: Synthesis of hydrochloride of intermediate 6

Dissolve 6-B (600 mg, 0.83 mmol) in 10 mL of 1,4-dioxane, add 10 mL of 4 mol/L hydrochloric acid 1,4-dioxane solution, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude intermediate 6 (0.65 g).

LCMS m/z = 626.3 [M+1] ⁺ .

Preparation of intermediate 7 (trans)

Step One: Preparation of 7-B

Dissolve the trifluoroacetate salt of crude product 11d (5.0 g) in 60 mL DMA, add sodium bicarbonate (1.68 g, 20.0 mmol), stir at room temperature for 15 min, then add 7-A (3.29 g, 9.58 mmol) ( The synthesis method (see WO2021158634), 1 mL acetic acid and 4 Å molecular sieve (5 g), stirred at room temperature for 2 h, then added sodium triacetyloxyborohydride (3.38 g, 15.95 mmol), and reacted at room temperature for 16 h. Add 150 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 100 mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/ethyl acetate (v /v) = 1:1), obtaining 7-B (1.0 g, yield: 14%).

Step 2: Preparation of Intermediate 7

Add 7-B (1.1 g, 1.52 mmol) to 30 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.86 g, 4.52 mmol), and react at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, 100 mL of ethyl acetate was added, and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate 7 (0.9 g).

Example 1: Preparation of Compound 1 (trans)

Step One: Preparation of 1A

2,6-Bis(benzyloxy)-3-bromopyridine (5.0 g, 13.50 mmol), pinacol diboronate (5.14 g, 20.24 mmol) and potassium acetate (2.65 g, 27.0 mmol) were added to the dry To 1,4-dioxane (20 mL), add Pd(dppf)Cl ₂ .DCM (1.10 g, 1.35 mmol), and react overnight at 100°C under nitrogen protection. Cool to room temperature, filter the reaction solution with diatomaceous earth, extract with ethyl acetate (50mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) = 1/20) to obtain 1A (4 g, yield: 71%).

LCMS m/z = 418.2 [M+H] ⁺ .

Step 2: Preparation of 1C

Under nitrogen protection, 1B (1.5 g, 4.75 mmol) (synthesized with reference to patent CN113512025), 1A (2.97 g, 7.12 mmol), Pd(dppf)Cl ₂ .DCM (CAS: 95464-05-4) (0.78 g, 0.96 mmol), cesium carbonate (3.10 g, 9.5 mmol) was added to 1,4-dioxane (45 mL) and water (10 mL), reacted at 105°C for 3 h, after the reaction was completed, it was cooled to room temperature, and water ( 50mL), extracted with ethyl acetate (30mL rate: 46.5%).

LCMS m/z = 480.1 [M+H] ⁺ .

Step 3: Preparation of 1D

Dissolve 1C (700 mg, 1.46 mmol) in anhydrous THF (20 mL), add lithium aluminum tetrahydrogen (166 mg, 4.37 mmol), and react at room temperature for 1 hour. At the end of the reaction, water (2 mL) was added to quench the reaction, filtered through diatomaceous earth, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V)=1/1) to obtain 1D (580 mg, yield: 88%)

LCMS m/z = 452.2 [M+H] ⁺ .

Step 4: Preparation of 1E

Dissolve 1D (600 mg, 1.33 mmol) in THF (30 mL), add triethylamine (673 mg, 6.65 mmol), stir at room temperature for 10 min, add TBSOTf (879 mg, 3.33 mmol), and react at room temperature for 1 h. After the reaction, it was concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) = 1/5) to obtain 1E (630 mg, yield: 84%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, 1H), 7.66 – 7.61 (m, 1H), 7.48 – 7.42 (m, 2H), 7.41 – 7.34 (m, 2H), 7.34 – 7.29 (m , 3H), 7.27 – 7.21 (m, 4H), 6.96 (dd, 1H), 6.53 (d, 1H), 5.45 (s, 2H), 5.41 (s, 2H), 5.07 (s, 2H), 4.43 ( s, 3H), 0.90 (s, 9H), 0.06 (s, 6H).

Step 5: Preparation of 1F

Dissolve 1E (630 mg, 1.11 mmol) in ethanol (30 mL), add palladium on carbon (10%) (1 g), replace with hydrogen three times, react at room temperature overnight, filter through diatomaceous earth, concentrate, and purify by silica gel column chromatography (Ethyl acetate/petroleum ether (V/V)=1/1) to obtain 1F (197 mg, yield: 46%).

LCMS m/z = 388.2 [M+H] ⁺ .

Step 6: Preparation of 1G

Dissolve 1F (197 mg, 0.51 mmol) in THF (5 mL), add tetrabutylammonium fluoride in THF solution (2.55 mL, 1 mol/L), react at room temperature for 1 hour, add water (20 mL) at the end of the reaction, Extract with ethyl acetate (20mL×3), dry with anhydrous sodium sulfate, filter, and concentrate to obtain 1G.

LCMS m/z = 274.1 [M+H] ⁺ .

Step 7: Preparation of 1H

Dissolve 1G obtained in the previous step in dichloromethane (5 mL), add Dess-Martin oxidant (432 mg, 1.02 mmol), and react at room temperature for 1 hour. Celite was suction filtered, concentrated, and purified by silica gel column chromatography (methanol/dichloromethane (V/V) = 1/20) to obtain 1H (100 mg, two-step yield: 72%).

LCMS m/z = 272.1 [M+H] ⁺ .

Step 8: Preparation of 1I

Dissolve 1H (50 mg, 0.18 mmol), methyl(piperidin-4-yl)aminocarboxylic acid tert-butyl ester (77 mg, 0.36 mmol) and glacial acetic acid (11 mg, 0.18 mmol) in anhydrous dichloroethane (5mL), add 4Å molecular sieve (1g), react at room temperature for 2 hours, add sodium triacetyloxyborohydride (76 mg, 0.36 mmol), and react at room temperature overnight. After the reaction is completed, filter through diatomaceous earth and concentrate. , silica gel preparation plate purification (methanol/dichloromethane (V/V) = 1/20) gave 1I (54 mg, yield: 64%).

LCMS m/z = 470.3 [M+H] ⁺ .

Step 9: Preparation of 1J

Dissolve 1I (52 mg, 0.11 mmol) in hydrogen chloride-dioxane (5 mL, 4 mol/L), react at room temperature for 1 h, concentrate after the reaction, add 5 mL of dioxane to the residue to reconstitute, and add 3 Ethylamine (0.5 mL) was concentrated to obtain 1J crude product.

Step 10: Preparation of Compound 1

Dissolve 1K (54 mg, 0.11 mmol) (synthesized with reference to patent WO2020113233), 1J crude product and glacial acetic acid (7 mg, 0.11 mmol) in anhydrous DMA (5 mL), add 4Å molecular sieve (1 g), and react at room temperature for 2 hours. , add sodium triacetoxyborohydride (35 mg, 0.17 mmol), and react at room temperature overnight. Filter, and use preparative HPLC for the filtrate (instrument: waters 2767 preparative liquid chromatography; column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoro Acetic acid)) purified and freeze-dried. The obtained solid was redissolved in dichloromethane (10 mL), water (5 mL) and saturated sodium bicarbonate solution (1 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1 (20 mg, yield: twenty two%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 9.49(d, 1H), 8.78(d, 1H), 8.37(d, 1H), 8.25(d, 1H), 7.67 – 7.60 (m, 1H), 7.25 – 6.94 (m, 3H), 6.89 – 6.40 (m, 1H), 5.30 – 5.02 (m, 1H), 4.83 – 4.71 (m, 1H), 4.41 – 4.33 (m, 1H ), 4.30 (s, 3H), 4.20 – 4.04 (m, 2H), 3.86 – 3.66 (m, 4H), 3.67 – 3.40 (m, 3H), 3.17(d, 2H), 2.94 – 2.83 (m, 2H) ), 2.70 – 2.61 (m, 2H), .2.37 – 2.28 (m, 2H), 2.21 – 2.16 (m, 3H), 2.07 – 1.81 (m, 8H), 1.75 – 1.56 (m, 4H), 1.41 – 1.32 (m, 2H), 1.08 – 0.91 (m, 2H).

LCMS m/z = 839.4 [M+H] ⁺ .

Example 2: Preparation of compound 2 (trans)

Step One: Preparation of 2A

Under nitrogen protection, add 3-bromo-1-methyl-7-nitro-1H-indazole (3 g, 11.72 mmol), 1A (7.3 g, 17.5 mmol), and dioxane in sequence into a 50 mL single-neck bottle. Ring (80 mL), water (20 mL), Pd(dppf)Cl ₂ .DCM (1.4 g, 1.71 mmol) and cesium carbonate (11.5 g, 35.3 mmol) were replaced with nitrogen three times and reacted at 100°C for 12 h. After the reaction is completed, cool to room temperature, pour the reaction solution into water, and extract three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2A (3.3 g, yield 60%).

LCMS m/z = 467.1 [M+H] ⁺ .

Step 2: Preparation of 2B

Dissolve 2A (1.6 g, 3.43 mmol), 10% palladium on carbon (0.9 g), and 10% palladium hydroxide on carbon (1.2 g) in 20 mL tetrahydrofuran and 20 mL methanol, replace with hydrogen three times, and react overnight at 30°C. . Cool to room temperature, filter with diatomaceous earth, wash the filter cake three times with methanol, combine the organic phases, dry over anhydrous sodium sulfate, and spin dry under reduced pressure to obtain 2B (650 mg, yield 73%).

LCMS m/z = 259.2 [M+H] ⁺ .

Step 3: Preparation of 2C

Dissolve 2B (250 mg, 0.97 mmol), KI (242 mg, 1.46 mmol), and iodine (371 mg, 1.46 mmol) in acetonitrile (5 mL) and cool to 0oC. Then slowly add isoamyl nitrite (171 mg, 1.46 mmol), and react at 30oC for 8 hours under nitrogen protection. Add 10 mL of saturated ammonium chloride solution, extract with dichloromethane, and concentrate the organic layer under reduced pressure. The residue is purified by silica gel column chromatography to obtain 2C (130 mg, yield: 36%).

LCMS m/z = 370.0 [M+H] ⁺ .

Step 4: 2D preparation

2C (130 mg, 0.35 mmol), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (101 mg, 0.42 mmol), CuI (13 mg, 0.07 mmol) ), PdCl ₂ (PPh ₃ ) ₂ (25 mg, 0.036 mmol), and triethylamine (1 mL) were dissolved in DMF (4 mL), replaced with nitrogen three times, and reacted at 60 ^o C for 6 h. Cool to room temperature, add 5 mL aqueous solution to dilute, extract with dichloromethane, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography to obtain 2D (91 mg, yield: 54%).

LCMS m/z = 381.2 [M-Boc+H] ⁺ .

Step 5: Preparation of 2E

Dissolve 2D (91 mg, 0.19 mmol) in methanol (1 mL), add 4N hydrochloric acid in dioxane (3 mL), react at room temperature for 1 h, concentrate under reduced pressure, add 5 mL of dichloromethane and 1 mL of methanol Re-dissolve, add 2 mL triethylamine, and concentrate under reduced pressure to obtain crude product 2E.

Step 6: Preparation of Compound 2

Dissolve the crude product of 2E in the previous step, 1K (102 mg, 0.21 mmol), and acetic acid (12.6 mg, 0.21 mmol) in DMA (5 mL), and add 4Å molecular sieve (2 g). After stirring at room temperature for 30 minutes, sodium triacetyloxyborohydride (57 mg, 0.27 mmol) was added, and the reaction was carried out at room temperature overnight. Add 20 mL saturated aqueous sodium bicarbonate solution and 20 mL methylene chloride for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM/MeOH (V/V)=100/1-20/1 ) to obtain compound 2 (30 mg, two-step yield: 19%).

LCMS m/z =850.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.77 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 ( m,1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.31 – 5.03 (m, 1H), 4.82 – 4.70 ( m, 1H), 4.54 (s, 2H), 4.41 (dd, 1H), 4.29 (s, 3H), 4.23 – 4.11 (m, 1H), 3.87 – 3.40 (m, 5H), 2.80 – 2.56 (m, 4H), 2.43 – 2.31 (m, 1H), 2.27 – 1.82 (m, 13H), 1.80 – 1.66 (m, 2H), 1.66 – 1.41 (m, 3H), 1.14 – 0.96 (m, 2H).

Example 3: Preparation of compound 3 (trans)

Step One: Preparation of 3A

2-(4-(hydroxymethyl)cyclohexyl)-6-morpholinyl-5-nitrosoindolin-1-one (500 mg, 1.33 mmol) (refer to patent WO2020264499 for the synthesis procedure), triethyl Amine (540 mg, 5.34 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0 ^o C, TBSOTf (700 mg, 2.65 mmol) was slowly added dropwise, and the reaction was carried out at room temperature under nitrogen protection for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3A (521 mg, yield: 80%).

LCMS m/z = 490.2 [M+H] ⁺ .

Step 2: Preparation of 3B

Dissolve 3A (521 mg, 1.06 mmol) in ethanol (10 mL) and water (2 mL), raise the temperature to 80°C, and add a mixture of ammonium chloride (280 mg, 5.23 mmol) and iron powder (300 mg, 5.37 mmol) , stir at 80°C for 1 hour, cool to room temperature, filter, wash the filter cake with 50 mL of methylene chloride, add 10 mL of saturated brine to the filtrate, separate the layers, dry the organic layer with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 3B (440 mg) .

LCMS m/z =460.3 [M+H] ⁺ .

Step 3: Preparation of 3C

5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g, 3.84 mmol) was dissolved in triturous chloride (30 mL), and stirred at 70°C for 2 h. Cool to room temperature and concentrate under reduced pressure to obtain crude product 3C (1.1g).

Step 4: 3D preparation

Under nitrogen atmosphere, 3B (440 mg, 0.96 mmol) and pyridine (150 mg, 1.9 mmol) were dissolved in anhydrous dichloromethane (10 mL), and cooled to 0 ^° C. Dissolve 3C crude product (500 mg) in anhydrous dichloromethane (4 mL), slowly add dropwise to the system, and react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3D (600 mg, yield: 89%).

LCMS m/z = 702.3 [M+H] ⁺ .

Step 5: Preparation of 3E

Dissolve 3D (600 mg, 0.85 mmol) in tetrahydrofuran (10 mL), cool to 0 ^° C, slowly add TBAF (1M, 1.71 mL), and react at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3E (372 mg, yield: 74%).

LCMS m/z = 588.2 [M+H] ⁺ .

Step 6: Preparation of 3F

3E (370 mg, 0.63 mmol) and Dess-Martin periodinane (530 mg, 1.25 mmol) were added to tetrahydrofuran (10 mL), and stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3F (350 mg, yield: 95%).

LCMS m/z = 586.3 [M+H] ⁺ .

Step 7: Preparation of Compound 3

Dissolve 2D (100 mg, 0.21 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (4 mL), react at room temperature for 1 h, concentrate under reduced pressure, add 10 mL of dichloromethane to reconstitute, add 3 mL Adjust triethylamine to alkalinity, concentrate under reduced pressure to obtain a compound residue, dissolve it in DMA (6 mL), and add 3F (120 mg, 0.20 mmol) and 4Å molecular sieve (2 g). Stir at room temperature for 30 min, add sodium triacetyloxyborohydride (58 mg, 0.27 mmol), and react at room temperature overnight. Add 20 mL saturated aqueous sodium bicarbonate solution and 20 mL methylene chloride for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified with a thin layer chromatography silica gel plate (mobile phase: DCM/MeOH (V/V) = 20/1) to obtain the compound. 3 (93 mg, yield: 49%).

LCMS m/z =950.4 [M+H] ⁺ .

Example 4: Preparation of trifluoroacetate salt (trans) of compound 4

Dissolve 1I (131 mg, 0.28 mmol) in hydrogen chloride-dioxane (5 mL, 4 mol/L) and react at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated, 5 mL of dioxane was added to the residue to redissolve, triethylamine (0.5 mL) was added, and the mixture was concentrated in vacuo. To this concentrate were added 3F, glacial acetic acid (17 mg, 0.28 mmol), anhydrous DMA (5 mL), and molecular sieves (2 g). After reacting at room temperature for 2 hours, sodium triacetyloxyborohydride (119 mg, 0.56 mmol) was added and the reaction was carried out at room temperature overnight. Filter, add saturated sodium bicarbonate solution (30 mL) to quench the reaction, extract with ethyl acetate (3 × 30 mL), wash with saturated brine (2 × 20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify with silica gel preparation plate (DCM : MeOH=10:1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparative liquid chromatography; chromatographic column: XBridge@PrepC18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) was purified and freeze-dried to obtain the trifluoroacetate salt of compound 4 (17 mg).

LCMS m/z = 470.4 [(M+2H)/2] ⁺ .

Example 6: Preparation of compound 6 (trans)

Step 1: Preparation of 6b

Dissolve 6a (6 g, 24.79 mmol) in 30 mL acetone, add potassium hydroxide (2.09 g, 37.25 mmol) at 0°C, stir for 15 min at 0°C, and add ethyl iodide (3.87 g, 24.81 mmol) dropwise. ), react at 20°C for 16 hours. The reaction system was concentrated under reduced pressure, 50 mL of ethyl acetate and 100 mL of water were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/ v) = 1:20), obtaining 6b (1.40 g, yield: 21%).

LCMS m/z = 270.0 [M+1] ⁺ .

Step 2: Preparation of 6c

Under nitrogen protection, add 6b (1.3 g, 4.81 mmol), 1A (3.01 g, 7.21 mmol), 1,4-dioxane (60 mL), water (20 mL), Pd ( dppf)Cl ₂ .DCM (0.39 g, 0.48 mmol) and cesium carbonate (4.70 g, 14.43 mmol) were replaced with nitrogen three times and reacted at 100°C for 12 h. Cool the reaction solution to room temperature, pour into 30 mL of water, extract three times with 200 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (ethyl acetate/petroleum ether) (v/v) = 1:5), 6c (1.5 g, yield: 65%) was obtained.

LCMS m/z = 481.1 [M+1] ⁺ .

Step 3: Preparation of 6d

Dissolve 6c (1.5 g, 3.12 mmol), 10% palladium on carbon (0.8 g) and 10% palladium hydroxide on carbon (1.0 g) in 30 mL of tetrahydrofuran and 30 mL of methanol, replace with hydrogen three times, and place under a hydrogen balloon atmosphere for 30 °C for 16 h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed three times with 50 mL of methanol. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6d (800 mg).

LCMS m/z = 273.2 [M+1] ⁺ .

Step 4: Preparation of 6e

Dissolve the above crude product 6d (400 mg), KI (0.37 g, 2.23 mmol), CuI (0.406 g, 2.13 mmol), and iodine element (560 mg, 2.21 mmol) in acetonitrile (5 mL), and cool to 0°C. Isoamyl nitrite (260 mg, 2.21 mmol) was slowly added, and the reaction was carried out at 30°C for 6 h under nitrogen protection. Add 10 mL of saturated ammonium chloride solution to the reaction solution, extract with 50 mL of dichloromethane, separate the layers, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate). Ester (v/v) =2:1-1:1), to obtain 6e (200 mg, two-step yield calculated from 6c: 33%).

LCMS m/z = 384.1 [M+1] ⁺ .

Step 5: Preparation of 6f

6e (100 mg, 0.26 mmol), 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester (see WO2021247899 for the synthesis method) (75 mg, 0.313 mmol), CuI ( 10 mg, 0.0525 mmol), PdCl ₂ (PPh ₃ ) ₂ (26 mg, 0.037 mmol) and triethylamine (0.13 g, 1.28 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, and reacted at 60°C for 6 h. . Cool the reaction solution to room temperature, add 5 mL of water, extract with 50 mL of methylene chloride, separate the layers, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 2:1-1:1), 6f (90 mg, yield: 70%) was obtained.

Step 6: 6g of trifluoroacetate

Dissolve 6f (90 mg, 0.18 mmol) in 5 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 6 g of crude trifluoroacetate (0.1 g).

LCMS m/z = 395.2 [M+1] ⁺ .

Step 7: Preparation of Compound 6

Dissolve 6g of the above crude product trifluoroacetate (100 mg) in 5 mL DMA, add sodium bicarbonate (30 mg, 0.36 mmol), stir at room temperature for 15 min, then add 6h (100 mg, 0.21 mmol), 0.04 mL acetic acid and 4 Å molecular sieve (2 g), stirred at room temperature for 30 min, then added sodium triacetyloxyborohydride (76 mg, 0.36 mmol), and reacted at room temperature for 16 h. Add 20 mL saturated sodium bicarbonate aqueous solution and 20 mL dichloromethane, separate the liquids, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (dichloromethane/methanol (v/v) = 100:1-20: 1), the obtained crude product was then subjected to chiral preparation and freeze-dried to obtain compound 6 (78.5 mg, yield: 43%).

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/isopropyl alcohol and acetonitrile mixed solvent, isotropic elution: sCO ₂ /isopropyl alcohol and acetonitrile mixed solvent = 2:3; flow rate: 100 mL/min.

Chirality analysis method of target compound:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak AD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 2:3; Retention time of target compound :0.875 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.55 – 9.45 (m, 1H), 8.78 (d, 1H), 8.42 – 8.34 (m, 1H), 8.29 – 8.21 (m , 1H), 7.84 – 7.73 (m, 1H), 7.57 – 7.46 (m, 1H), 7.30 – 6.93 (m, 2H), 6.92 – 6.40 (m, 1H), 5.35 – 5.00 (m, 1H), 4.84 – 4.66 (m, 3H), 4.53 (s, 2H), 4.46 – 4.37 (m, 1H), 4.25 – 4.08 (m, 1H), 3.90 – 3.38 (m, 5H), 2.80 – 2.56 (m, 4H) , 2.45 – 2.30 (m, 1H), 2.25 – 1.83 (m, 13H), 1.83 – 1.65 (m, 2H), 1.64 – 1.44 (m, 3H), 1.40 (t, 3H), 1.13 – 0.94 (m, 2H).

LCMS m/z = 864.3 [M+1] ⁺ .

Example 7: Preparation of Compound 7 (Trans)

Trans-5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-(4-((4-(( 3-(3-(2,6-dioxopiperidin-3-yl)-1-(methyl-d3)-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Compound 7 was obtained by using deuterated methyl iodide as the starting material and referring to the synthesis method of Example 6.

Step 1: Preparation of 7b

Dissolve 7a (6.00 g, 24.79 mmol) in 30 mL acetone, add potassium hydroxide (2.09 g, 37.25 mmol) at 0°C, stir for 15 min at 0°C, and add deuterated methyl iodide (3.60 g, 24.83 mmol), react at 20°C for 16 h. The reaction system was concentrated under reduced pressure, 50 mL of ethyl acetate and 100 mL of water were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/ v) = 1:20), obtaining 7b (4.90 g, yield: 76%).

Step 2: Preparation of 7c

Under nitrogen protection, add 7b (1.5 g, 5.79 mmol), 1A (3.62 g, 8.67 mmol), 1,4-dioxane (60 mL), water (20 mL), Pd (dppf )Cl ₂ .DCM (0.47 g, 0.578 mmol) and cesium carbonate (5.66 g, 17.37 mmol), replaced with nitrogen three times, and reacted at 100°C for 12 h. Cool the reaction solution to room temperature, pour the reaction solution into 30 mL of water, and extract three times with 200 mL of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (ethyl acetate). /petroleum ether (v/v) = 1:10), 7c (1.6 g, yield: 59%) was obtained.

LCMS m/z = 470.2 [M+1] ⁺ .

Step 3: Preparation of 7d

Dissolve 7c (1.6 g, 3.41 mmol), 10% palladium on carbon (0.8 g) and 10% palladium hydroxide on carbon (1.0 g) in 30 mL of tetrahydrofuran and 30 mL of methanol, replace the hydrogen three times, and place under a hydrogen balloon atmosphere for 30 °C for 16 h. Cool the reaction solution to room temperature, add 50 mL dichloromethane and stir for 5 min. Filter with diatomaceous earth. Wash the filter cake three times with 50 mL methanol. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 7d ( 850 mg).

LCMS m/z = 262.1 [M+1] ⁺ .

Step 4: Preparation of 7e

Dissolve the above crude product 7d (380 mg), KI (0.37 g, 2.23 mmol), CuI (0.406 g, 2.13 mmol), and iodine element (560 mg, 2.21 mmol) in acetonitrile (5 mL), and cool to 0°C. Isoamyl nitrite (260 mg, 2.21 mmol) was slowly added, and the reaction was carried out at 30 ^° C for 6 hours under nitrogen protection. Add 10 mL of saturated ammonium chloride solution to the reaction solution, extract with 50 mL of dichloromethane, separate the layers, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate). Ester (v/v) = 2:1-1:1), to obtain 7e (220 mg, two-step yield calculated from 7c: 39%).

Step 5: Preparation of 7f

7e (100 mg, 0.27 mmol), 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester (78 mg, 0.326 mmol), CuI (10 mg, 0.0525 mmol) , PdCl ₂ (PPh ₃ ) ₂ (20 mg, 0.0285 mmol) and triethylamine (0.14 g, 1.38 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, and reacted at 60°C for 6 h. Cool the reaction solution to room temperature, add 5 mL of water, extract with 50 mL of dichloromethane, separate the layers, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 2:1-1:1), 7f (110 mg, yield: 84%) was obtained.

Step 6: Preparation of 7g of trifluoroacetate

Dissolve 7f (110 mg, 0.23 mmol) in 5 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 7 g of crude trifluoroacetate (0.12 g).

Step 7: Preparation of Compound 7

Dissolve 7g of the above crude product trifluoroacetate (120 mg) in 5 mL DMA, add sodium bicarbonate (37 mg, 0.44 mmol), stir at room temperature for 15 min, then add 6h (130 mg, 0.273 mmol), 0.04 mL of acetic acid and 4Å molecular sieve (2 g), stirred at room temperature for 30 min, then added sodium triacetyloxyborohydride (97 mg, 0.458 mmol), and reacted at room temperature for 16 h. Add 20 mL saturated sodium bicarbonate aqueous solution and 20 mL dichloromethane to the reaction solution, separate the layers, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (dichloromethane/methanol (v/v) = 100: 1-20:1), the crude product was chiral prepared and lyophilized to obtain compound 7 (57.1 mg, yield: 25%).

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/isopropyl alcohol and acetonitrile mixed solvent, isotropic elution: sCO ₂ /isopropyl alcohol and acetonitrile mixed solvent = 2:3; flow rate: 100 mL/min.

Chirality analysis method of compound 7:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak AD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 2:3; Compound 7 retention time :0.989 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.77 (d, 1H), 8.42 – 8.35 (m, 1H), 8.29 – 8.22 (m ,1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.29 – 6.93 (m, 2H), 6.90 – 6.40 (m, 1H), 5.33 – 5.02 (m, 1H), 4.84 – 4.70 (m , 1H), 4.53 (s, 2H), 4.41 (dd, 1H), 4.24 – 4.10 (m, 1H), 3.97 – 3.40 (m, 5H), 2.80 – 2.56 (m, 4H), 2.43 – 2.31 (m , 1H), 2.27 – 1.82 (m, 13H), 1.80 – 1.66 (m, 2H), 1.66 – 1.41 (m, 3H), 1.14 – 0.96 (m, 2H).

LCMS m/z = 853.4 [M+1] ⁺ .

Example 8: Preparation of Compound 8 (Trans)

Compound 8 was obtained by using 8a+isopropane iodide as starting materials and referring to the synthesis method of Example 6.

Purification method of crude compound 8: The crude product is first prepared chirally and then prepared conventionally. The chiral isomer 1 (6.3 mg, yield: 4%) and chiral isomer 2 (9.6 mg, 4%) of compound 8 are obtained by freeze-drying. Yield: 6%).

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/isopropyl alcohol and acetonitrile mixed solvent, isotropic elution: sCO ₂ /isopropyl alcohol and acetonitrile mixed solvent = 65:35; flow rate: 140 mL/min.

Analytical methods for target compounds:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak AD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 3:2; Compound 8 chirality Retention time of isomer 1: 2.086 min. Retention time of chiral isomer 2 of compound 8: 2.687 min.

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was C18 packing material). Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.225% formic acid). Gradient elution method: acetonitrile gradient elution from 30% to 60% (elution time: 15 minutes).

NMR of chiral isomer 1 of compound 8:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.56 – 9.42 (m, 1H), 8.78 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.80 – 5.63 (m, 1H), 5.33 – 5.01 (m , 1H), 4.83 – 4.70 (m, 1H), 4.66 – 4.48 (m, 2H), 4.42 (dd, 1H), 4.30 – 4.10 (m, 1H), 3.96 – 3.40 (m, 5H), 2.80 – 2.56 (m, 3H), 2.45 – 1.65 (m, 17H), 1.65 – 1.41 (m, 9H), 1.15 – 0.95 (m, 2H).

LCMS m/z = 878.4 [M+1] ⁺ for chiral isomer 1 of compound 8.

NMR of chiral isomer 2 of compound 8:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.56 – 9.42 (m, 1H), 8.77 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.78 (d, 1H), 7.50 (d, 1H), 7.28 – 6.94 (m, 2H), 6.89 – 6.40 (m, 1H), 5.80 – 5.63 (m, 1H), 5.33 – 5.01 (m , 1H), 4.83 – 4.70 (m, 1H), 4.66 – 4.48 (m, 2H), 4.42 (dd, 1H), 4.30 – 4.10 (m, 1H), 3.96 – 3.40 (m, 5H), 2.80 – 2.56 (m, 3H), 2.45 – 1.65 (m, 17H), 1.65 – 1.41 (m, 9H), 1.15 – 0.95 (m, 2H).

LCMS m/z = 878.4 [M+1] ⁺ for chiral isomer 2 of compound 8.

Example 10: Preparation of Compound 10 (Trans)

Compound 10 uses (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (10a) as the starting material, and refers to the synthesis method of Example 12 to obtain compound 10 (20.5 mg, yield :11%).

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak OD Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia), isotropic elution: sCO ₂ /mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia) = 3:7 ;Flow rate: 100 mL/min.

Analytical methods for target compounds:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak OD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 2:3; Retention time of target compound :2.329 min.

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate). Gradient elution method: acetonitrile gradient elution from 50% to 80% (elution time: 10 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.78 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.33 – 5.01 (m, 1H), 4.95 – 4.70 (m , 2H), 4.61 (s, 2H), 4.46 – 4.36 (m, 1H), 4.29 (s, 3H), 4.24 – 4.10 (m, 1H), 3.88 – 3.40 (m, 5H), 2.95 – 2.55 (m , 4H), 2.45 – 1.65 (m, 16H), 1.65 – 1.45 (m, 1H), 1.11 – 0.95 (m, 2H).

LCMS m/z = 868.3 [M+1] ⁺ .

Example 11: Preparation of Compound 11 (Trans)

Using 11a and 3-bromoprop-1-yne as starting materials and referring to the synthesis method of Example 12, compound 11 (25.7 mg) was obtained.

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia), isotropic elution: sCO ₂ /mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia) = 3:7 ;Flow rate: 100 mL/min.

Analytical methods for target compounds:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak OD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 2:3; Retention time of target compound :2.263 min.

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate). Gradient elution method: acetonitrile gradient elution from 40% to 70% (elution time: 10 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.78 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.33 – 5.01 (m, 1H), 4.95 – 4.70 (m , 2H), 4.61 (s, 2H), 4.46 – 4.36 (m, 1H), 4.29 (s, 3H), 4.24 – 4.10 (m, 1H), 3.88 – 3.40 (m, 5H), 2.95 – 2.55 (m , 4H), 2.45 – 1.65 (m, 16H), 1.65 – 1.45 (m, 1H), 1.11 – 0.95 (m, 2H).

LCMS m/z = 868.3 [M+1] ⁺ .

Example 12: Preparation of Compound 12 (Trans)

Step One: Preparation of 12b

Add 12a (1.3 g, 5.93 mmol) to 50 mL tetrahydrofuran, cool to 0°C, add 0.22 g sodium hydride, keep stirring at 0°C for 30 min, then add 3-bromoprop-1-yne (0.77 g, 6.48 mmol), react at room temperature for 12 h. Add 100 mL saturated ammonium chloride solution to the reaction system, extract with 100 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) ) = 4:1), obtaining 12b (1.1 g, yield: 72%).

Step 2: Preparation of 12c

12b (0.07 g, 0.27 mmol) and 3-(7-iodo-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2C) (0.1 g, 0.27 mmol) Add to 5 mL DMF, add 1 mL triethylamine, CuI (0.02 g, 0.1 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.035 g, 0.05 mmol), replace with nitrogen three times, and react under nitrogen protection at 60°C for 4 h. The reaction solution was cooled to room temperature, 30 mL of ethyl acetate was added, the organic phase was washed with 50 mL of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/ v) = 2:1-1:1), get 12c (0.09 g, yield: 67%).

Step 3: Preparation of 12d trifluoroacetate

Add 12c (0.09 g, 0.18 mmol) to 3 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 12d (0.1 g).

LCMS m/z = 399.1 [M+1] ⁺ .

Step 4: Preparation of Compound 12

Add 2 mL triethylamine to the trifluoroacetate salt (0.1 g) of the above crude product 12d, add 5 mL DMA to dissolve, add 6h (0.087 g, 0.18 mmol), stir at room temperature for 3 h, then add triacetyloxy Sodium borohydride (0.042 g, 0.2 mmol), react at room temperature for 16 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was first prepared chirally and then prepared conventionally, and then lyophilized to obtain compound 12 (22 mg, yield: 14%).

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/isopropyl alcohol and acetonitrile mixed solvent, isotropic elution: sCO ₂ /isopropyl alcohol and acetonitrile mixed solvent = 2:3; flow rate: 100 mL/min.

Analytical methods for target compounds:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak AD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 2:3; Retention time of target compound :1.16 min.

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile gradient elution from 45% to 75% (elution time: 15 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.77 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.33 – 5.01 (m, 1H), 4.85 – 4.70 (m , 1H), 4.63 (s, 2H), 4.59 – 4.35 (m, 2H), 4.29 (s, 3H), 4.24 – 4.08 (m, 1H), 3.88 – 3.40 (m, 5H), 3.10 – 2.95 (m , 1H), 2.78 – 2.55 (m, 3H), 2.45 – 1.37 (m, 17H), 1.11 – 0.95 (m, 2H).

LCMS m/z = 434.8 [M/2+1] ⁺ .

Example 13: Preparation of Compound 13 (Trans)

Using 13a+3-bromoprop-1-yne as starting materials and referring to the synthesis method of Example 12, compound 13 (10.6 mg) was obtained.

Chiral preparation method:

Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, and the preparative column model was Chiralpak AD Column;

Mobile phase system: sCO ₂ (supercritical CO ₂ )/mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia), isotropic elution: sCO ₂ /mixed solvent of isopropanol and acetonitrile (containing 0.1% ammonia) = 2:3 ;Flow rate: 100 mL/min.

Analytical methods for target compounds:

Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiralpak AD-3; Specifications: 50×4.6 mm ID, 3 μm; Mobile phase A: sCO ₂ (supercritical CO ₂ ); Mobile phase B: mixed solvent of isopropyl alcohol and acetonitrile (Containing 0.05% diethylamine); Column temperature: 35°C; Flow rate: 3 mL/min; Wavelength: 220 nm; Elution program: Isogradient elution: Mobile phase A:B = 1:1; Retention time of target compound :2.345 min.

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate). Gradient elution method: acetonitrile gradient elution from 40% to 70% (elution time: 15 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.56 – 9.42 (m, 1H), 8.78 (d, 1H), 8.42 – 8.35 (m, 1H), 8.28 – 8.22 (m ,1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 – 6.42 (m, 1H), 5.33 – 5.01 (m, 1H), 4.85 – 4.70 (m , 1H), 4.63 (s, 2H), 4.59 – 4.35 (m, 2H), 4.29 (s, 3H), 4.24 – 4.08 (m, 1H), 3.88 – 3.40 (m, 5H), 3.10 – 2.95 (m , 1H), 2.78 – 2.55 (m, 3H), 2.45 – 1.37 (m, 17H), 1.11 – 0.95 (m, 2H).

LCMS m/z = 868.3 [M+1] ⁺ .

Example 14: Preparation of trifluoroacetate salt (Trans) of compound 14

Step One: Preparation of 14b

14a (1.1 g, 4.09 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (0.49 g, 4.94 mmol), rac-BINAP (0.25 g, 0.40 mmol) ), cesium carbonate (4.0 g, 12.3 mmol) and Pd2(dba)3 (0.75 g, 0.82 mmol) were dissolved in 30 mL dioxane, replaced with nitrogen three times, and reacted at 100°C for 20 h. The reaction solution was cooled to room temperature, 50 mL of water was slowly added, extracted with ethyl acetate (50 mL), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether ( v/v) = 0:1-7:3), 14b (0.40 g, yield: 34%) was obtained.

LCMS m/z = 288.1 [M+1] ⁺ .

Step 2: Preparation of 14c

14b (400 mg, 1.39 mmol) and lithium hydroxide monohydrate (290 mg, 6.91 mmol) were dissolved in methanol (10 mL) and water (20 mL), and reacted at 70°C for 20 h. Cool the reaction solution to room temperature, concentrate under reduced pressure, add 20 mL of water, adjust the pH to 5 with 1 mol/L hydrochloric acid aqueous solution, extract with 50 mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Crude product (200 mg). The above crude product (170 mg), trans-(4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (see WO2021247897 for synthesis method) (160 mg , 0.65 mmol) and N-methylimidazole (190 mg, 2.31 mmol) were dissolved in acetonitrile (5 mL), then TCFH (270 mg, 0.96 mmol) was added, and the reaction was carried out at room temperature for 20 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 14c (150 mg, yield: 47%).

LCMS m/z = 487.2 [M+1] ⁺ .

Step 3: Preparation of trifluoroacetate salt of compound 14

Dissolve 14c (200 mg, 0.41 mmol) in dichloromethane (3 mL), add Dess-Martin oxidizing agent (340 mg, 0.80 mmol), and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain intermediate 14A (100 mg). The above crude product 2E (46 mg) was dissolved in DMA (3 mL), intermediate 14A (60 mg) and 0.1 mL acetic acid were added, and after stirring at room temperature for 30 min, sodium triacetyloxyborohydride (31 mg, 0.146 mmol), react at room temperature for 16 h. Slowly add 10 mL saturated aqueous sodium bicarbonate solution to the reaction solution, extract twice with 20 mL ethyl acetate, combine the organic phases, wash the organic phase with 30 mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product Separate and purify using silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9). The obtained crude product is then prepared conventionally and lyophilized to obtain the trifluoroacetate salt of compound 14 (9 mg).

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% trifluoroacetic acid). Gradient elution method: acetonitrile gradient elution from 25% to 40% (elution time 16 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.34 (s, 1H), 8.58 – 8.42 (m, 2H), 8.11 (s, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 7.33 – 6.93 (m, 3H), 6.78 – 6.66 (m, 1H), 4.82 – 4.66 (m, 2H), 4.60 (s, 2H), 4.42 (dd, 1H), 4.35 – 4.27 (m, 3H), 4.27 – 4.15 (m, 1H), 4.05 – 3.76 (m, 2H), 3.74 – 3.65 (m, 1H), 3.65 – 3.33 (m, 3H), 3.18 – 2.93 (m, 5H ), 2.77 – 2.57 (m, 2H), 2.45 – 1.60 (m, 15H), 1.30 – 1.09 (m, 2H). LCMS m/z = 849.2 [M+1] ⁺ .

Example 15: Preparation of trifluoroacetate salt (Trans) of compound 15

Using 15a+(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane as the starting material and referring to the synthesis method of Example 14, the trifluoroacetate salt of compound 15 (10 mg) was obtained .

Purification method: The crude product is separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9). The crude product is then prepared conventionally, and then the preparation solution is adjusted to acidity with trifluoroacetic acid and frozen. Drying gave compound 15 as the trifluoroacetate salt (10 mg).

Conventional preparation method:

Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the preparative column model was Phenomenex C18. Preparation method: Dissolve the crude product with acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate). Gradient elution method: acetonitrile gradient elution from 30% to 60% (elution time: 10 minutes).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.35 – 9.17 (m, 2H), 8.40 (s, 1H), 8.29 (s, 1H), 7.80 (d, 1H), 7.53 (d, 1H), 7.30 – 6.93 (m, 2H), 5.33 – 5.12 (m, 1H), 4.77 – 4.70 (m, 1H), 4.60 (s, 2H), 4.47 – 4.37 (m, 1H), 4.35 – 4.15 (m, 4H), 4.07 – 3.65 (m, 5H), 3.63 – 3.32 (m, 2H), 3.15 – 2.92 (m, 4H), 2.78 – 2.55 (m, 2H), 2.46 – 1.65 (m , 15H), 1.28 – 1.10 (m, 2H). LCMS m/z = 868.3 [M+1] ⁺ .

Example 16: Preparation of Compound 16 (Trans) Step One: Preparation of 16b

16a (4.0 g, 16.53 mmol), cyclopropylboronic acid (4.28 g, 49.83 mmol), sodium carbonate (5.28 g, 49.82 mmol), Cu(OAc) ₂ (3.00 g, 16.52 mmol) and 2,2'- Bipyridyl (2.60 g, 16.65 mmol) was dissolved in 60 mL DCE, nitrogen was replaced three times, and the reaction was carried out at 80°C for 6 h under nitrogen protection. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 16b (1.7 g, yield: 36%).

Step 2: Preparation of 16c

Under nitrogen protection, add 16b (1.5 g, 5.32 mmol), 1A (3.33 g, 7.98 mmol), dioxane (60 mL), water (20 mL), and Pd (dppf) into a 100 mL single-mouth bottle. Cl ₂ •CH ₂ Cl ₂ (CAS: 95464-05-4) (0.43 g, 0.53 mmol) and cesium carbonate (5.20 g, 15.96 mmol) were replaced with nitrogen three times and reacted at 100°C for 12 h under nitrogen protection. Cool the reaction system to room temperature, pour into 50 mL of water, extract with ethyl acetate (100 mL×3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column ( Petroleum ether:ethyl acetate (v/v) =5:1) to obtain 16c (1.8 g, yield: 69%).

LCMS m/z = 493.1 [M+1] ⁺ .

Step 3: Preparation of 16d

Dissolve 16c (1.7 g, 3.45 mmol) and 10% Pd/C (0.8 g) in 30 mL tetrahydrofuran and 30 mL methanol, replace hydrogen three times, and react at 30°C for 16 h. The reaction system was filtered through diatomaceous earth, and the filter cake was washed with methanol (30 mL×3). The filtrate was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 16d (850 mg).

LCMS m/z = 285.1 [M+1] ⁺ .

Step 4: Preparation of 16e

Dissolve the above crude product 16d (400 mg), KI (0.35 g, 2.11 mmol), CuI (0.40 g, 2.10 mmol), and I ₂ (0.54 g, 2.13 mmol) in 10 mL acetonitrile, cool to 0°C, and slowly add Isoamyl nitrite (250 mg, 2.13 mmol), react at 30°C for 6 hours under nitrogen protection. Add 10 mL saturated aqueous ammonium chloride solution to the reaction system, extract with 50 mL dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/ v) = 2:1-1:1), to obtain 16e (220 mg, two-step yield calculated from compound 16c: 34%).

LCMS m/z = 396.0 [M+1] ⁺ .

Step 5: Preparation of 16f

16e (150 mg, 0.38 mmol), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (0.11 g, 0.46 mmol), CuI (14 mg, 0.074 mmol) , PdCl ₂ (PPh ₃ ) ₂ (27 mg, 0.0385 mmol) and TEA (0.19 g, 1.88 mmol) were dissolved in 5 mL DMF, replaced with nitrogen three times, and reacted at 60°C for 6 h. Cool the reaction system to room temperature, add 5 mL of water, and extract with 30 mL of dichloromethane. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether:ethyl acetate (v/ v) = 2:1-1:1), 16f (130 mg, yield: 68%) was obtained.

Step 6: Preparation of 16 g of trifluoroacetate

Dissolve 16f (120 mg, 0.24 mmol) in 5 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain 16 g of crude trifluoroacetate (0.13 g).

LCMS m/z = 407.2 [M+1] ⁺ .

Step 7: Preparation of Compound 16

Dissolve 16g of crude trifluoroacetate (130 mg) in 5 mL of DMA, add sodium bicarbonate (40 mg, 0.48 mmol), stir at room temperature for 15 min, then add 6h (140 mg, 0.29 mmol), 0.04 mL Acetic acid and 4 Å molecular sieve (2 g) were stirred at room temperature for 30 min, then sodium triacetyloxyborohydride (102 mg, 0.48 mmol) was added, and the reaction was carried out at room temperature for 16 h. Add 20 mL saturated sodium bicarbonate aqueous solution and 20 mL dichloromethane to the reaction solution, separate the layers, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (dichloromethane/methanol (v/v) = 100: 1-20:1), and the crude product was subjected to HPLC purification to obtain compound 16 (50.4 mg, yield: 20%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.55 – 9.45 (m, 1H), 8.78 (d, 1H), 8.38 (d, 1H), 8.25 (d, 1H), 7.75 (d, 1H), 7.52 (d, 1H), 7.27 – 6.92 (m, 2H), 6.90 – 6.40 (m, 1H), 5.33 – 5.02 (m, 1H), 4.83 – 4.70 (m, 1H), 4.51 (s, 2H), 4.43 – 4.32 (m, 1H), 4.23 – 4.01 (m, 2H), 3.88 – 3.40 (m, 5H), 2.78 – 2.55 (m, 4H), 2.44 – 1.40 (m, 19H ), 1.30 – 0.94 (m, 6H).

LCMS m/z = 876.3 [M+1] ⁺ .

Example 17: Preparation of Compound 17 (Trans)

Dissolve the hydrochloride (130 mg) of the above crude intermediate 6 in 5 mL acetonitrile, add the above crude intermediate 2 (61 mg) and TCFH (67 mg, 0.24 mmol), and add NMI (0.11 g, 1.34 mmol) , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v) = 12:1), the obtained crude product was subjected to chiral preparation, and the chiral isomer 1 of compound 17 was obtained (37.5 mg, the two-step yield calculated from compound 2-B: 18 %) and chiral isomer 2 (18.4 mg, two-step yield from compound 2-B: 9%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector Column: Chiralpak IE-3; specifications: 150×4.6 mm I.D., 3 μm; mobile phase A: acetonitrile; mobile phase B: methanol; column temperature: 35°C; flow rate: 1 mL /min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 3.368 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.28 (s, 1H), 8.88 (d, 1H), 8.38 – 8.29 (m, 2H), 7.79 (d, 1H), 7.52 (d, 1H), 7.26 – 6.90 (m, 3H), 4.94 – 4.72 (m, 1H), 4.61 (s, 2H), 4.58 – 4.48 (m, 1H), 4.48 – 4.34 (m, 3H), 4.29 (s, 3H), 4.24 – 4.04 (m, 2H), 3.85 – 3.71 (m, 2H), 3.30 – 3.22 (m, 2H), 2.95 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H ), 2.46 – 2.26 (m, 2H), 2.24 – 2.10 (m, 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.13 – 0.94 (m, 2H).

LCMS m/z = 924.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 4.029 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.28 (s, 1H), 8.88 (d, 1H), 8.38 – 8.29 (m, 2H), 7.79 (d, 1H), 7.52 (d, 1H), 7.26 – 6.90 (m, 3H), 4.94 – 4.72 (m, 1H), 4.60 (s, 2H), 4.58 – 4.48 (m, 1H), 4.48 – 4.34 (m, 3H), 4.29 (s, 3H), 4.24 – 4.04 (m, 2H), 3.85 – 3.71 (m, 2H), 3.30 – 3.22 (m, 2H), 2.95 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H ), 2.46 – 2.26 (m, 2H), 2.24 – 2.10 (m, 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.13 – 0.94 (m, 2H).

LCMS m/z = 924.4 [M+1] ⁺ .

Example 18: Preparation of Compound 18 (Trans)

Dissolve the hydrochloride (130 mg) of the above crude intermediate 6 in 5 mL acetonitrile, add the above crude intermediate 1 (56 mg) and TCFH (67 mg, 0.24 mmol), and add NMI (0.11 g, 1.34 mmol) , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v) = 12:1), the obtained crude product was subjected to chiral preparation, and the chiral isomer 1 of compound 18 was obtained (17.8 mg, the two-step yield calculated from compound 1-D: 9 %) and chiral isomer 2 (16.2 mg, two-step yield from compound 1-D: 9%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analysis method of target compound: Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35℃; flow rate: 1 mL/min; wavelength: 220 nm; elution program: isogradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 6.469 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.32 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.60 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.29 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.5 [M+1] ⁺ .

Retention time of chiral isomer 2: 7.967 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.32 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.60 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.29 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.4 [M+1] ⁺ .

Example 19: Preparation of Compound 19 (Trans)

Dissolve the hydrochloride (130 mg) of the above crude intermediate 6 in 5 mL acetonitrile, add the above crude intermediate 3 (53 mg) and TCFH (67 mg, 0.24 mmol), and add NMI (0.11 g, 1.34 mmol) , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v) = 12:1), the obtained crude product was subjected to chiral preparation, and the chiral isomer 1 of compound 19 was obtained (18.2 mg, the two-step yield calculated from compound 3-A: 7 %) and chiral isomer 2 (12.5 mg, two-step yield from compound 3-A: 5%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector Column: Chiralpak IE-3; specifications: 150×4.6 mm I.D., 3 μm; mobile phase A: acetonitrile; mobile phase B: methanol; column temperature: 35°C; flow rate: 1 mL /min; wavelength: 220 nm; elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.313 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.61 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 6.457 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.60 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

The obtained chiral isomer 2 was prepared acidically to obtain the trifluoroacetate salt of chiral isomer 2.

Acidic preparation method:

Instrument and preparation column: Shimadzu LC-20AP was used to prepare the liquid phase, and the preparation column model was Welch Xtimate C18; mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile, gradient elution: water (containing 0.1% trifluoroacetic acid) Acetic acid)/acetonitrile = 18:82-48:52; flow rate: 25 mL/min.

NMR data of trifluoroacetate salt of chiral isomer 2:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 9.35 (s, 1H), 8.82 (d, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.81 ( d, 1H), 7.53 (d, 1H), 7.27 – 7.07 (m, 2H), 6.91 (d, 1H), 4.90 – 4.56 (m, 3H), 4.53 – 3.82 (m, 10H), 3.65 – 3.46 ( m, 4H), 3.20 – 3.08 (m, 2H), 3.07 – 2.90 (m, 2H), 2.76 – 2.56 (m, 2H), 2.45 – 1.68 (m, 14H), 1.60 – 1.46 (m, 1H), 1.34 – 1.10 (m, 2H).

Example 20: Preparation of compound 20 (Trans)

Dissolve the hydrochloride (130 mg) of the above crude intermediate 6 in 5 mL acetonitrile, add the above crude intermediate 5 (53 mg) and TCFH (67 mg, 0.24 mmol), and add NMI (0.11 g, 1.34 mmol) , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v) = 12:1), the obtained crude product was subjected to chiral preparation, and the chiral isomer 1 of compound 20 was obtained (10.3 mg, the two-step yield calculated from compound 5-A: 4 %) and chiral isomer 2 (9.8 mg, two-step yield from compound 5-A: 4%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector Column: Chiralpak IE-3; specifications: 150×4.6 mm I.D., 3 μm; mobile phase A: acetonitrile; mobile phase B: methanol; column temperature: 35°C; flow rate: 1 mL /min; wavelength: 220 nm; elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.229 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 (d, 1H), 4.93 – 4.72 (m, 2H), 4.61 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.94 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 6.378 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.60 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.94 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Example 21: Preparation of compound 21 (Trans)

Dissolve the hydrochloride (130 mg) of the above crude intermediate 6 in 5 mL acetonitrile, add the above crude intermediate 4 (56 mg) and TCFH (67 mg, 0.24 mmol), and add NMI (0.11 g, 1.34 mmol) , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column ( Dichloromethane/methanol (v/v) = 12:1), the obtained crude product was subjected to chiral preparation, and the chiral isomer 1 of compound 21 was obtained (18.3 mg, the two-step yield calculated from compound 4-C: 5 %) and chiral isomer 2 (20.3 mg, two-step yield from compound 4-C: 6%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector Column: Chiralpak IE-3; specifications: 150×4.6 mm I.D., 3 μm; mobile phase A: acetonitrile; mobile phase B: methanol; column temperature: 35°C; flow rate: 1 mL /min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 6.563 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.33 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.61 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.30 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 8.07 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.33 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.61 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.30 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.4 [M+1] ⁺ .

Example 22: Preparation of compound 22 (Trans)

Add the above crude intermediate 7 (0.12 g) to 5 mL acetonitrile, add the above crude intermediate 2 (0.08 g) and TCFH (0.084 g, 0.3 mmol), add NMI (0.08 g, 0.97 mmol) at 0°C, Reaction at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral preparation to obtain chiral isomer 1 (21.6 mg, yield: 8%) and chiral isomer 2 (22.7 mg, yield: 8%) of compound 22, respectively. 8%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 3.449 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.28 (s, 1H), 8.88 (d, 1H), 8.38 – 8.29 (m, 2H), 7.78 (d, 1H), 7.52 (d, 1H), 7.26 – 6.90 (m, 3H), 4.94 – 4.72 (m, 1H), 4.61 (s, 2H), 4.58 – 4.48 (m, 1H), 4.48 – 4.34 (m, 3H), 4.29 (s, 3H), 4.24 – 4.04 (m, 2H), 3.85 – 3.71 (m, 2H), 3.30 – 3.22 (m, 2H), 2.95 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H ), 2.46 – 2.26 (m, 2H), 2.24 – 2.10 (m, 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.13 – 0.94 (m, 2H).

LCMS m/z = 924.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 4.165 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.28 (s, 1H), 8.88 (d, 1H), 8.38 – 8.29 (m, 2H), 7.79 (d, 1H), 7.52 (d, 1H), 7.26 – 6.90 (m, 3H), 4.94 – 4.72 (m, 1H), 4.61 (s, 2H), 4.58 – 4.48 (m, 1H), 4.48 – 4.34 (m, 3H), 4.29 (s, 3H), 4.24 – 4.04 (m, 2H), 3.85 – 3.71 (m, 2H), 3.30 – 3.22 (m, 2H), 2.95 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H ), 2.46 – 2.26 (m, 2H), 2.24 – 2.10 (m, 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.13 – 0.94 (m, 2H).

LCMS m/z = 924.4 [M+1] ⁺ .

Example 23: Preparation of compound 23 (Trans)

Add the above crude intermediate 7 (0.12 g) to 5 mL acetonitrile, add the above crude intermediate 1 (0.073 g) and TCFH (0.084 g, 0.3 mmol), add NMI (0.08 g, 0.97 mmol) at 0°C, Reaction at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral preparation to obtain chiral isomer 1 (20.5 mg, two-step yield from compound 1-D: 8%) and chiral isomer of compound 23, respectively. 2 (17.8 mg, two-step yield from compound 1-D: 7%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; wavelength: 220 nm; elution program: isogradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 6.645 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.33 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.92 (d, 1H), 4.94 – 4.71 (m, 1H), 4.61 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.29 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.5 [M+1] ⁺ .

Retention time of chiral isomer 2: 8.228 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.80 (d, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.60 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.29 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.4 [M+1] ⁺ .

Example 24: Preparation of compound 24 (Trans)

Add the above crude intermediate 7 (0.12 g) to 5 mL acetonitrile, add the above crude intermediate 3 (0.07 g) and TCFH (0.084 g, 0.3 mmol), add NMI (0.08 g, 0.97 mmol) at 0°C, Reaction at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral preparation to obtain chiral isomer 1 (30.5 mg, two-step yield from compound 3-A: 8%) and chiral isomer of compound 24, respectively. 2 (28 mg, two-step yield from compound 3-A: 8%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.434 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.89 (d, 1H), 4.93 – 4.72 (m, 2H), 4.61 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 6.706 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.61 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Example 25: Preparation of compound 25 (Trans)

Add the above crude intermediate 7 (0.12 g) to 5 mL acetonitrile, add the above crude intermediate 5 (0.07 g) and TCFH (0.084 g, 0.3 mmol), add NMI (0.08 g, 0.97 mmol) at 0°C, Reaction at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral preparation to obtain chiral isomer 1 (25 mg, two-step yield from compound 5-A: 19%) and chiral isomer of compound 25, respectively. 2 (26.4 mg, two-step yield calculated from compound 5-A: 20%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.364 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.61 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.94 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 6.619 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.34 (s, 1H), 8.81 (d, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.79 ( d, 1H), 7.52 (d, 1H), 7.27 – 6.94 (m, 2H), 6.90 (d, 1H), 4.93 – 4.72 (m, 2H), 4.60 (s, 2H), 4.52 – 4.10 (m, 7H), 4.03 – 3.92 (m, 1H), 3.87 – 3.70 (m, 1H), 3.67 – 3.46 (m, 4H), 3.20 – 3.06 (m, 1H), 3.05 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.75 – 2.56 (m, 3H), 2.44 – 2.30 (m, 2H), 2.25 – 2.10 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.66 (m, 6H ), 1.65 – 1.50 (m, 1H), 1.12 – 0.94 (m, 2H).

LCMS m/z = 886.4 [M+1] ⁺ .

Example 26: Synthesis of Compound 26 (Trans)

Add the above crude intermediate 7 (0.12 g) to 5 mL acetonitrile, add the above crude intermediate 4 (0.073 g) and TCFH (0.084 g, 0.3 mmol), add NMI (0.08 g, 0.97 mmol) at 0°C, Reaction at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral preparation to obtain chiral isomer 1 (25.2 mg, two-step yield from compound 4-C: 12%) and chiral isomer of compound 26, respectively. 2 (18.9 mg, two-step yield from compound 4-C: 9%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; wavelength: 220 nm; elution program: isogradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 6.733 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 9.33 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.92 (d, 1H), 4.94 – 4.71 (m, 1H), 4.61 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.29 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.4 [M+1] ⁺ .

Retention time of chiral isomer 2: 8.385 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.32 (s, 1H), 8.81 (d, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.84 – 7.73 (m, 1H), 7.56 – 7.48 (m, 1H), 7.28 – 6.96 (m, 2H), 6.91 (d, 1H), 4.94 – 4.71 (m, 1H), 4.60 (s, 2H), 4.46 – 4.24 (m, 6H), 4.24 – 4.10 (m, 1H), 4.00 – 3.91 (m, 1H), 3.87 – 3.53 (m, 3H), 3.50 – 3.42 (m, 2H), 3.30 (s, 3H), 3.21 – 3.07 (m, 1H), 3.06 – 2.93 (m, 1H), 2.93 – 2.76 (m, 1H), 2.76 – 2.55 (m, 3H), 2.45 – 2.25 (m, 2H), 2.25 – 2.10 (m , 4H), 2.10 – 1.95 (m, 2H), 1.95 – 1.65 (m, 6H), 1.65 – 1.49 (m, 1H), 1.12 – 0.95 (m, 2H).

LCMS m/z = 900.5 [M+1] ⁺ .

Example 27: Preparation of compound 27 (Trans)

Step One: Preparation of 27a

Combine 16e (600 mg, 1.52 mmol), 10b (470 mg, 1.83 mmol), CuI (58 mg, 0.30 mmol), PdCl ₂ (PPh ₃ ) ₂ (110 mg, 0.157 mmol) and TEA (0.77 g, 7.61 mmol). ) was dissolved in 20 mL DMF, replaced with nitrogen three times, and reacted at 60°C for 5 h. The reaction system was cooled to room temperature, 80 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (dichloromethane/ Ethyl acetate (v/v) = 1:1), giving 27a (550 mg, yield: 69%).

Step 2: Preparation of trifluoroacetate salt of 27b

Dissolve 27a (500 mg, 0.95 mmol) in 10 mL dichloromethane, add 4 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 27b (0.65 g).

LCMS m/z = 425.2 [M+1] ⁺ .

Step 3: Synthesis of Compound 27

Dissolve the trifluoroacetate salt (650 mg) of the above crude product 27b in 20 mL DMA, add sodium bicarbonate (160 mg, 1.90 mmol), stir at room temperature for 15 min, then add 6h (560 mg, 1.16 mmol), 0.15 mL acetic acid and 4 Å molecular sieve (2 g), stirred at room temperature for 2 h, then added sodium triacetyloxyborohydride (410 mg, 1.93 mmol), and reacted at room temperature for 16 h. Add 40 mL saturated sodium bicarbonate aqueous solution and 20 mL dichloromethane to the reaction system, separate the liquids, concentrate the organic phase under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (dichloromethane/methanol (v/v) = 100: 1-20:1), the obtained crude product was subjected to chiral preparation, and chiral isomer 1 (270 mg, yield: 26%) and chiral isomer 2 (200 mg, yield: 19) of compound 27 were obtained respectively. %).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.139 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.49 (d, 1H), 8.77 (d, 1H), 8.38 (d, 1H), 8.25 (d, 1H), 7.76 ( d, 1H), 7.53 (d, 1H), 7.28 – 6.93 (m, 2H), 6.90 – 6.40 (m, 1H), 5.35 – 5.02 (m, 1H), 4.95 – 4.70 (m, 2H), 4.59 ( s, 2H), 4.43 – 4.32 (m, 1H), 4.24 – 4.02 (m, 2H), 3.88 – 3.40 (m, 5H), 2.95 – 2.54 (m, 4H), 2.45 – 1.45 (m, 17H), 1.27 – 0.94 (m, 6H).

LCMS m/z = 894.5 [M+1] ⁺ .

Retention time of chiral isomer 2: 5.982 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.49 (d, 1H), 8.77 (d, 1H), 8.38 (d, 1H), 8.25 (d, 1H), 7.76 ( d, 1H), 7.53 (d, 1H), 7.28 – 6.93 (m, 2H), 6.90 – 6.40 (m, 1H), 5.35 – 5.02 (m, 1H), 4.95 – 4.70 (m, 2H), 4.59 ( s, 2H), 4.43 – 4.32 (m, 1H), 4.24 – 4.02 (m, 2H), 3.88 – 3.40 (m, 5H), 2.95 – 2.54 (m, 4H), 2.45 – 1.45 (m, 17H), 1.27 – 0.94 (m, 6H).

LCMS m/z = 894.5 [M+1] ⁺ .

Example 28: Preparation of compound 28 (Trans)

Using (3R,4S)-3-fluoro-4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester +16e as the starting material, refer to the synthesis method of Example 27, Compound 28 was obtained.

Purification method: The crude product is separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 100:1-20:1). The crude product is subjected to chiral preparation to obtain chiral isomer 1 of compound 28 ( 290 mg, yield: 24%) and chiral isomer 2 (250 mg, yield: 21%).

Chiral preparation method:

Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, and the preparative column model was Chiralpak IE, 250×30 mm, 10 μm; mobile phase system: acetonitrile/methanol, isotropic elution: acetonitrile/methanol = 1:1 ;Flow rate: 80 mL/min.

Analytical methods for target compounds:

Instrument: Shimadzu LC-20AB with PDA detector; Chromatographic column: Chiralpak IE-3; Specification: 150×4.6 mm I.D., 3 μm; Mobile phase A: acetonitrile; Mobile phase B: methanol; Column temperature: 35°C; Flow rate: 1 mL/min; Wavelength: 220 nm;

Elution program: iso-gradient elution: mobile phase A:B = 3:7;

Retention time of chiral isomer 1: 5.277 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.49 (d, 1H), 8.77 (d, 1H), 8.38 (d, 1H), 8.25 (d, 1H), 7.76 ( d, 1H), 7.53 (d, 1H), 7.28 – 6.93 (m, 2H), 6.90 – 6.40 (m, 1H), 5.35 – 5.02 (m, 1H), 4.95 – 4.70 (m, 2H), 4.59 ( s, 2H), 4.43 – 4.32 (m, 1H), 4.24 – 4.02 (m, 2H), 3.88 – 3.40 (m, 5H), 2.95 – 2.54 (m, 4H), 2.45 – 1.45 (m, 17H), 1.27 – 0.94 (m, 6H).

LCMS m/z = 447.9 [M/2 +1] ⁺ .

Retention time of chiral isomer 2: 6.017 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 9.50 (d, 1H), 8.78 (d, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.76 ( d, 1H), 7.53 (d, 1H), 7.28 – 6.93 (m, 2H), 6.90 – 6.40 (m, 1H), 5.35 – 5.02 (m, 1H), 4.95 – 4.70 (m, 2H), 4.59 ( s, 2H), 4.43 – 4.32 (m, 1H), 4.24 – 4.02 (m, 2H), 3.88 – 3.40 (m, 5H), 2.95 – 2.54 (m, 4H), 2.45 – 1.45 (m, 17H), 1.27 – 0.94 (m, 6H).

LCMS m/z = 894.5 [M+1] ⁺ .

Biological test examples

Test Example 1: Study on IRAK4 degradation activity in hPBMC cells (24 hours)

hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood from healthy volunteers was collected and hPBMC were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured in 37 ℃, 5% CO ₂ incubator. Cells were plated in 24-well plates at 1 × 10 ⁶ cells/well. After plating, compounds of different concentrations were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, cells were collected, added with RIPA lysis buffer (Beyotime, Cat. P0013B), lysed on ice for 20 minutes, centrifuged at 12,000 rpm and 4°C for 10 minutes, and supernatant protein samples were collected and analyzed with BCA kit (Beyotime, Cat. P0009) After protein quantification, the protein was diluted to 1 mg/mL. The expression of IRAK4 (CST, Cat. 4363S) and internal reference cofilin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). Use compass software to calculate the expression level of IRAK4 relative to the internal reference. Use formula (1) to calculate the remaining amount IRAK4% of IRAK4 protein at different doses relative to the vehicle control group, and use formula (2) to calculate the degradation amount of IRAK4 protein at different doses relative to the vehicle control group, where IRAK4 _{administration} is at different doses. The expression level of IRAK4 in the drug group and IRAK4 _in the vehicle group are the expression levels of IRAK4 in the vehicle control group. Use Graphpad Prism 8 software to fit the IRAK4 degradation amount-drug concentration curve to calculate DC ₅₀ .

IRAK4% = IRAK4 _{administration} /IRAK4 _vehicle × 100% Formula 1

IRAK4 degradation % = 100% - IRAK4% Formula 2

Table 1 Degradation activity of test compounds on IRAK4 protein in hPBMC cells at 100 nM Compound number IRAK4 protein remaining amount IRAK4% Compound 1 B Compound 2 A Compound 6 A Compound 7 A Chiral isomer 1 of compound 8 B Compound 10 A Compound 11 A Compound 12 B Compound 13 B Trifluoroacetate salt of compound 15 B Compound 16 A

Note: In Table 1, A≤10%, 10%＜B≤50%, 50%＜C

Table 2 DC50 of test compounds for IRAK4 protein degradation in hPBMC cells Compound number DC ₅₀ (nM) Chiral isomer 1 of compound 19 <20 Chiral isomer 2 of compound 19 <20 Chiral isomer 1 of compound 20 <20 Chiral isomer 2 of compound 20 <20 Chiral isomer 2 of compound 23 <20 Chiral isomer 1 of compound 24 <20 Chiral isomer 1 of compound 25 <20 Chiral isomer 2 of compound 25 <20

Conclusion: The compound of the present invention has a certain degradation effect on IRAK4 protein in hPBMC cells at 24 hours.

Test Example 2: Mouse Pharmacokinetic Test

Experimental animals: male ICR mice, ~25 g, 6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, 6 ICR mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.

Table 2.1 Dosing information Group quantity Dosing Information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the invention or control compounds 2.5 0.5 5 plasma veins G2 3 Compounds of the invention or control compounds 10 1 10 plasma Oral administration

Intravenous administration vehicle: 5%DMA+5%Solutol+90%Saline;

Intragastric administration vehicle: 5% DMSO+30%PEG400+65%(20%SBE-CD);

(DMSO: Dimethylstyrene; DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; PEG400: Polyethylene glycol 400; SBE-β-CD: Sulfobutyl -β-cyclodextrin; Saline: physiological saline;)

Before and after administration, 0.15 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4 ^° C for 10 min to collect plasma. The time points for intravenous and intragastric blood collection were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. All samples were stored at -60 ^o C before analysis. Samples were quantitatively analyzed using LC-MS/MS.

Table 2.2 Pharmacokinetic parameters of the compounds of the present invention in mouse plasma test compound Mode of administration* AUC _0-t (ng/mL·h) Compound 10 ig (10 mg/kg) 17480±5264 Compound 11 ig (10 mg/kg) 8748±4649 Chiral isomer 1 of compound 19 ig (10 mg/kg) 13407±4034 Trifluoroacetate salt of chiral isomer 2 of compound 19 ig (10 mg/kg) 8304±2852 Chiral isomer 2 of compound 20 ig (10 mg/kg) 3938±1106 Control Compound 1 ig (10 mg/kg) 2322±146

*Note: Compounds are administered i.g. (gavage);

Conclusion: The compound of the present invention has good oral absorption in mice.

Test example 3. hERG potassium ion channel function test

Experimental platform: electrophysiology manual patch clamp system

Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is made from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after filling the electrode internal liquid is about 2-5 MΩ. Just insert the glass microelectrode into the amplifier probe. Connect to patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer. The sampling frequency is 10 kHz and the filtering frequency is 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV, and the step voltage of induced hERG potassium current (I _hERG ) was given from -80 mV to +20 mV for 2 seconds, and then repolarized to -50 mV. mV, lasts for 1s and then returns to -80 mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ≥ 2).

Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) at different compound concentrations was calculated using the following formula:

Inhibition % = [1 – (I / Io)]×100%

Among them, Inhibition % represents the inhibition percentage of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.

Compound IC ₅₀ was calculated by fitting the following equation using GraphPad Prism 5 software:

Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Among them, X is the Log value of the detected concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively.

Table 3. IC50 value of the test substance on the inhibitory effect of hERG potassium channel current compound IC ₅₀ (μM) Compound 10 >30 Compound 11 >30 Chiral isomer 1 of compound 19 >20 Trifluoroacetate salt of chiral isomer 2 of compound 19 >40 Compound 12 >30 Compound 2 B Chiral isomer 1 of compound 20 >40 Chiral isomer 2 of compound 20 >40 Chiral isomer 2 of compound 23 >40 Chiral isomer 1 of compound 24 >40 Chiral isomer 1 of compound 25 >40 Chiral isomer 2 of compound 25 >40 Control Compound 1 0.6421

Note: 1<B≤30 in Table 3

Conclusion: The compounds of the present invention have no obvious inhibitory effect on hERG potassium channels.

The structure of Comparative Compound 1 is as follows, and its synthesis refers to patent WO2020113233A1.

Test Example 4: Rat Pharmacokinetic Test

Test animals: male SD rats, about 200 g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.

Table 4.1 Dosing information Group quantity Dosing Information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the invention or control compounds 2.5 0.5 5 plasma veins G2 3 Compounds of the invention or control compounds 10 1 10 plasma Oral administration

Intravenous administration vehicle: 5%DMA+5%Solutol+90%Saline;

Intragastric administration vehicle: 5% DMSO+30%PEG400+65%(20%SBE-CD);

(DMSO: Dimethylstyrene; DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; PEG400: Polyethylene glycol 400; SBE-β-CD: Sulfobutyl -β-cyclodextrin; Saline: physiological saline;)

Before and after administration, 0.15 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 6000 rpm and 4 ^° C for 5 min to collect plasma. The time points for intravenous and intragastric blood collection were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -60 ^o C before analysis. Samples were quantitatively analyzed using LC-MS/MS.

Conclusion: The compound of the present invention has good oral absorption in rats.

Test Example 5: Beagle Pharmacokinetic Test

Experimental animals: male beagle dogs, about 8-11 kg, 6/compound. Purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the day of the test, 6 beagle dogs were randomly divided into groups according to body weight. The subjects were fasted for 14 to 18 hours one day before administration and fed 4 hours after administration.

Table 5.1 Dosing information Group quantity Dosing information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the invention or control compounds 1 1 1 plasma veins G2 3 Compounds of the invention or control compounds 5 1 5 plasma Oral administration

Intravenous administration vehicle: 10%DMA+5%Solutol+85%Saline;

Intragastric administration vehicle: 5% DMSO+30%PEG400+65%(20%SBE-CD);

Before and after administration, take 1 mL of blood from the jugular vein or limb veins, place it in an EDTAK2 centrifuge tube, centrifuge at 5000 rpm, 4 ^o C for 10 minutes, and collect the plasma. The time points for intravenous and intragastric blood collection were 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -60 ^o C before analysis. Samples were quantitatively analyzed using LC-MS/MS.

Conclusion: The compounds of the present invention have good oral absorption in dogs.

Test Example 6: Monkey Pharmacokinetic Test

Experimental animals: male cynomolgus monkeys, about 3-5 kg, 3-6 years old, 6/compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

Experimental method: On the day of the experiment, 6 monkeys were randomly divided into groups according to body weight. The subjects were fasted for 14 to 18 hours one day before administration and fed 4 hours after administration.

Table 6.1 Dosing information Group quantity Dosing Information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the invention or control compounds 1 1 1 plasma veins G2 3 Compounds of the invention or control compounds 5 1 5 plasma Oral administration

Intravenous administration vehicle: 10%DMA+5%Solutol+85%Saline;

Intragastric administration vehicle: 5% DMSO+30%PEG400+65%(20%SBE-CD);

Before and after administration, take 1 mL of blood from the veins of the limbs, place it in an EDTAK2 centrifuge tube, and centrifuge at 5000 rpm and 4 ^o C for 10 min to collect plasma. The time points for intravenous and intragastric blood collection were 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -60 ^o C before analysis. Samples were quantitatively analyzed using LC-MS/MS.

Conclusion: The compound of the present invention has good oral absorption in monkeys.

Test Example 7: Liver Microsome Stability Test

This experiment uses five types of hepatic microsomes from humans, monkeys, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.

At 37°C, 1 µM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC was used. -MS/MS method detects the concentration of the test substance in the sample, calculates T _1/2 based on the ln value of the drug remaining rate in the culture system and the culture time, and further calculates the liver microsome intrinsic clearance rate CL _{int (mic)} and liver intrinsic clearance rate Clearance CL _int(Liver) .

Conclusion: The compounds of the present invention have good liver microsome stability.

Test Example 8: CYP450 Enzyme Inhibition Test

The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were co-cultured with human liver microsomes and test substances of different concentrations. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, , by processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC ₅₀ value, and evaluate the effect of the test substance on Inhibitory potential of each CYP enzyme isoform.

Conclusion: The compounds of the present invention have no obvious inhibitory effect on CYP450 enzyme subtypes.

Test Example 9: Caco2 Penetration Test

The experiment used a single layer of Caco-2 cells cultured in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4± 0.05) into the administration port hole on the apical or basal side. Add DMSO-containing transport buffer solution to the corresponding receiving port hole. After incubating for 2 hours at 37±1°C, remove the cell plate and take appropriate amounts of samples from the top and bottom ends into a new 96-well plate. Acetonitrile containing internal standard was then added to precipitate the protein. Samples were analyzed using LC MS/MS and the concentrations of compounds of the invention and control compounds were determined. Concentration data are used to calculate apparent permeability coefficients for transport from the apical side to the basal side and from the basal side to the apical side of a monolayer of cells, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of culture was evaluated by the leakage of Lucifer Yellow.

Conclusion: The compounds of the present invention have good CaCO ₂ permeability.

Test Example 10: Study on Ikaros degradation activity in hPBMC cells (24 hours)

hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood from healthy volunteers was collected and hPBMC were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO ₂ incubator. Cells were plated in 24-well plates at 1×106 cells/well. After plating, compounds of different concentrations were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, cells were collected, added with RIPA lysis buffer (Beyotime, Cat. P0013B), lysed on ice for 20 minutes, centrifuged at 12,000 rpm and 4°C for 10 minutes, and supernatant protein samples were collected and analyzed with BCA kit (Beyotime, Cat. P0009) After protein quantification, dilute the protein to 1 mg/mL. The expression of Ikaros (CST, Cat. #14859S) and internal control β-actin (CST, Cat. #4970S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). Use compass software to calculate the expression of Ikaros relative to the internal reference. Use equation (3) to calculate the remaining amount of Ikaros protein at different doses relative to the vehicle control group, and use equation (4) to calculate the degradation amount of Ikaros protein at different doses relative to the vehicle control group, and obtain the maximum degradation rate of Ikaros protein by the drug. (Dmax).

Ikaros remaining amount % = Ikaros _compound /Ikaros _solvent × 100% Formula (3)

Ikaros degradation amount %=100%-Formula (3) Formula (4)

Conclusion: The compound of the present invention has no obvious degradation effect on Ikaros protein in hPBMC cells.

Test Example 11: Study on Aiolos degradation activity in hPBMC cells (24 hours)

hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood from healthy volunteers was collected and hPBMC were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO ₂ incubator. Cells were plated in 24-well plates at 1×106 cells/well. After plating, compounds of different concentrations were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, collect the cells, add RIPA lysis buffer (Beyotime, Cat. P0013B), lyse on ice for 20 minutes, centrifuge at 12000 rpm, 4°C for 10 minutes, collect the supernatant protein sample, and use BCA kit (Beyotime, Cat. P0009) After protein quantification, dilute the protein to 1 mg/mL. The expression of Aiolos (CST, Cat. #15103) and internal control β-actin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). Use compass software to calculate the expression of Aiolos relative to the internal reference. Use equation (5) to calculate the remaining amount of Aiolos protein at different doses relative to the vehicle control group, and use equation (6) to calculate the degradation amount of Aiolos protein at different doses relative to the vehicle control group, and obtain the maximum degradation rate of Aiolos protein by the drug. (Dmax).

Aiolos remaining amount % = Aiolos _compound /Aiolos _solvent × 100% Formula (5)

Aiolos degradation amount %=100%-Formula (5) Formula (6)

Conclusion: The compound of the present invention has no obvious degradation effect on Aiolos protein in hPBMC cells.

Test Example 12: Study on IRAK4 degradation activity in hPBMC cells (4 hours)

hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood from healthy volunteers was collected and hPBMC were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO ₂ incubator. Cells were plated in 24-well plates at 1×106 cells/well. After plating, compounds of different concentrations were added and cultured in a 37°C, 5% CO ₂ incubator for 4 hours. After the culture, cells were collected, added with RIPA lysis buffer (Beyotime, Cat. P0013B), lysed on ice for 20 minutes, centrifuged at 12,000 rpm and 4°C for 10 minutes, and supernatant protein samples were collected and analyzed with BCA kit (Beyotime, Cat. P0009) After protein quantification, dilute the protein to 1 mg/mL. The expression of IRAK4 (CST, Cat. 4363S) and internal reference cofilin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). Use compass software to calculate the expression level of IRAK4 relative to the internal reference. Use equation (7) to calculate the remaining amount of IRAK4 protein at different doses relative to the vehicle control group, and use equation (8) to calculate the degradation amount of IRAK4 protein at different doses relative to the vehicle control group, where the IRAK4 _compound is IRAK4 in the different dose administration group Expression level, IRAK4 _vehicle is the expression level of IRAK4 in the vehicle control group. Use Graphpad Prism 8 software to fit the IRAK4 degradation amount-drug concentration curve to calculate DC ₅₀ .

IRAK4 remaining amount % = IRAK4 _compound /IRAK4 _solvent × 100% Formula (7)

IRAK4 degradation amount %=100%-Formula (7) Formula (8)

Conclusion: The compound of the present invention has a certain degradation effect on IRAK4 protein in hPBMC cells at 4 h.

without

without

Claims (14)

A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I), BLK (I) ; L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH ₂ ) _q -, O, -( CH ₂ ) _q NR ^L -, NR ^L C=O, C=ONR ^L , C=O, -R ^L C=CR ^L -, C≡C or bond; R ^L is selected from H or C _1-6 alkyl ; Cy1, Cy2, Cy3, and Cy4 are each independently selected from the group consisting of bonds, 4-7-membered heteromonocyclic rings, 4-10-membered heterocyclic rings, 5-12-membered heterospirocyclic rings, 7-10-membered heterobridged rings, 3-7 Monocyclic alkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged cycloalkyl, 5-10-membered heteroaryl or 6-10-membered aryl, the above Aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring are optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, C ( =O)OH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl or C _1-4 alkoxy substituents Substituted, the heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S or N; B is selected from or ; B1 and B3 are each independently selected from C _6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, and the heteroaryl or heterocyclic group contains 1 to 4 selected from O , S or N heteroatoms; R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , -N(R ^b21 ) ₂ , C _6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by 0 to 4 Each is selected from H, F, Cl, Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _1-4 alkyl Substituted with an oxygen group, C _3-6 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or R ^b7a substituent, the heteroaryl or heterocyclic group contains 1 to 4 Heteroatom selected from O, S or N; R ^b7a is selected from C _1-4 alkyl, -C _3-6 cycloalkyl, 4-10 membered heterocyclyl, -C _1-4 alkylene -C _{3 -6} cycloalkyl, -C _1-4 alkylene, -4-10 membered heterocyclyl, -OC _3-6 cycloalkyl, -O-4-10 membered heterocyclyl, -NH-C _3-6 Cycloalkyl, -NH-4-10-membered heterocyclyl, -N(C _1-4 alkyl)-C _3-6 cycloalkyl or -N(C _1-4 alkyl)-4-10-membered heterocyclyl Ring group, the R ^b7a is optionally 1 to 4 selected from H, F, Cl, Br, I, OH, =O, -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 4-10 membered heterocyclyl substituents, the heterocyclyl contains 1 to 4 selected from O , S or N heteroatoms; R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, OH, -C(=O)N(R ^b21 ) ₂ , -N(R ^b21 ) ₂ , CN, CF ₃ , C(=O)OH, CHF ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n -R ^b21 , -OR ^b21 , C _6-10 aryl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group, the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group or The heterocyclyl group is optionally further selected from 0 to 4 members from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, Substituted with substituents of C _1-4 alkoxy, C _3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N; R ^b21 are each independently selected from H, C _1-6 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _6-10 aromatic base, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted by 0 to 4 Selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, CF ₃ , C(=O)OH, C _1-4 alkyl, C _3-6 cycloalkyl or C _1- Substituted with ₄ alkoxy substituents, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; n is selected from 0, 1, 2, 3 or 4; K Selected from , , or ; ^Rk1 is each independently selected from H, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the Alkyl, cycloalkyl or heterocycloalkyl is optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, CF ₃ , C _1-6 alkyl, C _{1 -6} alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or C _3-6 cycloalkyl substituents; R ^k2 and R ^k3 are each independently selected from H, F, Cl, Br , I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C(=O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, the alkyl Or the alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH ₂ ; or two R ^k3 and the carbon atom or ring directly connected to the two The skeleton together forms a 3-6-membered carbocyclic ring or a 3-7-membered heterocyclic ring, which is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, NH _2. Substituted with CN, C(=O)OH, C(=O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 selected from Heteroatom of O, S or N; q is selected from 0, 1, 2, 3 or 4; n1, n2, n6 are each independently selected from 0, 1, 2 or 3; p2 and p3 are each independently selected from 0, 1, 2, 3 or 4; Optionally, 0 to 50 H in the compound represented by general formula (I) are replaced by 0 to 50 D. The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein Cy1, Cy2, Cy3 and Cy4 are each independently selected Self-bonding, 4-7 membered nitrogen-containing heteromonocyclic ring, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered nitrogen-containing heterospirocyclic ring, 7-10-membered nitrogen-containing heterobridged ring, 3-7-membered monocycloalkane base, 4-10 membered paracycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, 5-10 membered heteroaryl group or 6-10 membered aryl group, the heteromonocyclic ring, Heterocycle, heterobridged ring, heterospirocycle, cycloalkyl, aryl or heteroaryl are optionally further selected from 0 to 4 from H, F, Cl, Br, I, OH, C(=O)OH , CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl or C _1-4 alkoxy substituent, so The heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N. The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R ^L is selected from H, methyl or ethyl ; Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepine Cyclopentyl, piperidyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl base, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidine, cyclopropylazetidine, cyclobutyl cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclopentyl azetidinyl, cyclopentyl azetidinyl, cyclopentyl Azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, azetidinyl azetidinyl, azetidinyl Azocyclopentyl, azetidinyl and azetihexyl, azetidinyl and azetipentyl, azetidinyl and azetidine, azetidinyl and azetidine, Cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclobutylspiroazetidinyl Pentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, azetidinylspiroazetidinyl, azetidine Basespiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl Jiji, , , , , , , , , , , , , , , , , , , or , , when substituted, optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , C(=O)OH, CN, =O, C _1-4 alkyl, Substituted with halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl or C _1-4 alkoxy substituents; B1 and B3 are each independently selected from pyrazolyl, oxazolyl, di Oxazolyl, oxadiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyridyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl or ; R ^b1 and R ^b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH ₂ , CN, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, methoxy , ethoxy, phenyl, pyrrolyl, pyridyl, morpholinyl, , , , , , , , , , , , , , , , , , or , the methyl, ethyl, methoxy, ethoxy, phenyl, pyrrolyl, pyridyl or morpholinyl group is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, CN, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, C _1-4 alkyl, C _1-4 alkyl Substituted by an oxygen group, a C _3-6 cycloalkyl group or a substituent of R ^b7a ; or R ^b1 and R ^b7 are each independently selected from azetidinyl, azetanyl, piperidinyl, piperazinyl, Morpholinyl or 2-oxa-5-azabicyclo[2.2.1]heptyl, the R ^b1 and R ^b7 are optionally 1 to 4 selected from F, Cl, Br, I, OH, = O, CN, CF ₃ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHCH ₂ C _3-6 cycloalkyl, halogen-substituted C _1-4 alkyl, cyano group Substituted C _1-4 alkyl, -C _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 alkoxy, -CH ₂ -OC _1-4 alkyl, -CH ₂ - C _3-6 cycloalkyl, -OC _3-6 cycloalkyl, -NH-C _3-6 cycloalkyl, C _3-6 cycloalkyl, -CH ₂ -4 to 7-membered heterocycloalkyl, - O-4 to 7-membered heterocycloalkyl, -NH-4 to 7-membered heterocycloalkyl 4- to 7-membered heterocycloalkyl substituents substituted, the heterocyclic group contains 1 to 4 selected from O, S or N heteroatoms; R ^b2 and R ^b6 are each independently selected from H, F, Cl, Br, I, =O, CF ₃ , CHF ₂ , OH, NH ₂ , NH (methyl), NH (ethyl) base), NH (propyl), NH (isopropyl), N (methyl) ₂ , N (ethyl) ₂ , CN, methyl, ethyl, methoxy, ethoxy, propoxy, Isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyl The baseoxy group, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituent; R ^k1 is each independently selected from H, methyl, ethyl, propyl, isopropyl , vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepanyl, pipera Aldyl, oxetanyl, oxetanyl or oxetanyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, azetanyl, piperidinyl, oxetanyl, oxetanyl or oxetanyl is optionally further selected from 0 to 4 from H, F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl or C _3-6 ring Substituted with alkyl substituents; R ^k2 and R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, C(=O)OH, C( =O)NH ₂ , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy or ethoxy is optionally further substituted by 0 to 4 selected from H, F, Cl , Br, I, OH or NH ₂ substituents; p2 or p3 are each independently selected from 0, 1 or 2. The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein Cy1, Cy2, Cy3 and Cy4 are each independently selected Self-bonded or substituted or unsubstituted one of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , when substituted, optionally further substituted by 0 to 4 substituents selected from H, F, CF ₃ , methyl, =O, hydroxymethyl, C(=O)OH, CN or NH ₂ ; B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein L is selected from the group consisting of bonds, -Cy1-, -Cy1 -Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Cy1-Cy2 -Ak3-Cy4-, -Cy1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Cy3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Ak4-Ak5 -, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2 -Cy3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Ak5-, -Cy1- Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak4-Cy4-, -Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2- Ak3-, -Ak1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4-, -Ak1-Ak2-Ak3-Cy3-Ak4-, -Ak1-Cy1- Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-Ak3-, -Ak1-Cy1-Ak2-Ak3-Ak4-, -Ak1-Cy1-, -Ak1-Cy1-Ak2- Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2- Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3-Ak4-, or -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-; Ak1 , Ak2, Ak3, Ak4, Ak5 are each independently selected from O, C≡C, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ , CH ₂ N(CH ₃ ) , CH ₂ CH ₂ N(CH ₃ ), N(CH ₃ ), NH, C(=O), C(=O)N(CH ₃ ), N(CH ₃ )C(=O), C(= O)NH or NHC(=O). The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , or ; J ₁ are each independently selected from , or ; J ₂ are independently selected from , , , , , , , , , , or ; J ₃ are independently selected from , , , , or ; J ₄ are independently selected from , , , , or ; J ₅ are each independently selected from ; Alternatively, L is selected from ; R ^d is selected from H or D, and at least one R ^d is selected from D; d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9. The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, L is selected from the groups shown in Table L-1, where the left side of the group is connected to B. The compound according to any one of claims 5-7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein K is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table P-1. A pharmaceutical composition, including the compound described in any one of claims 1-9 or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical Acceptable carrier, preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound described in any one of claims 1-9 or its stereoisomers, deuterated products, solvates, prodrugs, and metabolites , pharmaceutically acceptable salts or co-crystals. A compound described in any one of claims 1 to 9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or a drug described in claim 10 Use of the composition in the preparation of medicaments for treating diseases related to IRAK4 activity or expression level. A compound described in any one of claims 1 to 9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or a drug described in claim 10 Use of the composition in the preparation of a medicament for treating diseases associated with inhibition or degradation of IRAK4. According to the use according to claim 12, the disease is selected from autoimmune diseases, inflammatory diseases or cancer. A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any one of claims 1-9 or its stereoisomers, deuterated products, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals or the pharmaceutical composition described in claim 10, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably autoimmune disease, inflammatory disease or cancer.